SK17432001A3 - Beta2-adrenoceptor agonists, process for the preparation and use thereof and pharmaceutical composition comprising same - Google Patents

Abstract

Compounds of formula I in free or salt or solvate form, where Ar is a group of formula II where Y is carbon or nitrogen and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X, n, p, q and r are as defined in the specification, their preparation and their use as pharmaceuticals, particularly for the treatment of obstructive or inflammatory airways diseases.

Description

Beta-2-adrenoceptor agonists, process for their preparation, their use and pharmaceutical composition containing them

Technical field

The invention relates to organic compounds having good agonist activity on 32-adrenoceptors. The invention further relates to the preparation of these compounds and their use as pharmaceutical compositions.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I

in free form or in the form of salts or in the form of solvates in which:

Ar is a group of formula II

n:

R ¹ is a hydrogen atom, a hydroxyl group or an alkoxy group,

R ² and R ³ are each independently hydrogen or alkyl,

R ⁴ , R ³ , R ° and R 'are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, alkoxy, aryl, alkyl, alkyl substituted with one or more halogen atoms, one or more hydroxy or alkoxy groups, alkyl interrupted by one or more hetero atoms, alkenyl, trialkylsilyl, carboxy, alkoxycarbonyl or a group -CONR ⁿ R ^12, wherein R ¹¹ and R ¹² are independently H or C R ⁴ and R ³ , R ⁵ and R ⁶ or R ⁶ and R ⁷ together with the carbon atom to which they are attached represent a carbocyclic or heterocyclic ring,

R ⁸ is halogen, -OR ¹³ , -CH 2 OR ¹³ or -NHR ^{x 3} wherein R ¹³ is hydrogen, alkyl, alkyl interrupted by one or more heteroatoms, -COR ¹⁴ wherein R ¹⁴ is hydrogen , -N (R ¹⁵ ) R ¹⁶ , alkyl or alkyl interrupted by one or more heteroatoms, or aryl and R ¹⁵ and R ¹⁶ are each independently hydrogen, alkyl interrupted by one or more heteroatoms, or - C (= NH) R ¹⁷ , -SOR ^X, or -SO 2 R ¹⁷ , wherein R ¹⁷ is an alkyl or alkyl group interrupted by one or more heteroatoms,

R ⁹ is hydrogen or R ⁸ is -NHR ¹⁸ wherein -NHR ¹⁸ and R 'together with the carbon atom to which they are attached are 5- or

6-membered heterocyclic ring,

R ¹⁰ is -OR ¹⁹ or -NHR ¹⁹ where R ¹⁹ is hydrogen, alkyl, alkyl interrupted by one or more heteroatoms, or -COR ²⁰ wherein R ²⁰ is -N (R ^-1 ) R ²² , an alkyl or alkyl group interrupted by one or more heteroatoms or an aryl group, and R ²¹ and R ² are independently hydrogen, alkyl or alkyl interrupted by one or more heteroatoms.

X is a halogen atom or a halomethyl group or an alkyl group,

Y is a carbon or nitrogen atom, n is 1 or 2, p is zero if Y is a nitrogen atom or 1 when Y is a carbon atom, q and r are zero or 1, the sum of q + r being 1 or 2 and the carbon labeled the asterisk * has the R or S configuration, or mixtures thereof, when R 1 is a hydroxyl group or an alkoxy group.

The terms used in this specification have the following meanings:

"Alkyl means an unbranched or branched alkyl group which is, for example, an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, unbranched or branched pentyl, unbranched or branched hexyl, unbranched or branched heptyl, unbranched or branched octyl, unbranched or branched nonyl or unbranched or branched decyl. Preferred alkyl groups are alkyl groups having 1 to 4 carbon atoms. Alkyl groups substituted with one or more halogen atoms or one or more hydroxyl groups or alkoxy groups may be the above-mentioned alkyl groups having 1 to 10 carbon atoms, substituted with one or more halogen atoms, preferably a chlorine or fluorine atom, with one or more hydroxyl groups or one or more alkoxy groups having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms.

"Alkyl interrupted by one or more heteroatoms" means an unbranched or branched alkyl chain, for example of 2 to 10 carbon atoms, in which one or more pairs of carbon atoms are bonded by -O-, -NR-, -S-, -S (= O) Or -SO 2 -, wherein R is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms (preferably 1 to 4 carbon atoms). Such preferred groups are alkoxyalkyl groups, preferably C 1 -C 4 alkoxyalkyl groups in each alkyl.

"Alkoxy means a straight or branched chain alkoxy group, for example, a C 1 -C 10 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy; butoxy or unbranched or branched pentoxy groups, hexyloxy groups, heptyloxy groups, octyloxy groups, nonyloxy groups or decyloxy groups. Preferred are alkoxy groups having 1 to 4 carbon atoms.

"Alkenyl represents a straight or branched chain alkenyl group which may be unsubstituted or substituted, for example by one or more halogen atoms, one or more alkoxy groups which may contain 2 to 10 carbon atoms, such as a vinyl group, a propenyl group; -propenyl, 1-butenyl, isobutenyl or branched or branched pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decenyl groups. Preferred alkenyl groups are alkenyl groups having 2 to 4 carbon atoms.

"Aryl represents an unsubstituted or substituted aryl group, for example an unsubstituted phenyl or naphthyl group or a phenyl or naphthyl group substituted with one or more substituents, for example 1 to 4 substituents selected from the group consisting of C 1 -C 4 alkyl, hydroxyl, alkoxy C 1 -C 4, halogen or C 1 -C 4 haloalkyl. A preferred aryl group is an unsubstituted phenyl group or a phenyl group substituted with 1 or 2 substituents selected from the group consisting of (C 1 -C 4) alkyl or halogen.

"Alkylene represents a straight or branched alkylene group, for example an alkylene group having 1 to 10 carbon atoms, such as a methylene group, an ethylene group,

1,2-propylene, 1,3-propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene or decylene. Preferred alkylene groups are C 1 -C 4 alkylene groups.

"Alkenylene represents a straight or branched chain alkenylene group such as a C 2 -C 10 alkenylene group such as a vinylene group, a propenylene group, a butenylene group, a pentenylene group, a hexenylene group, a heptenylene group, an octenylene group, a decenylene group, a nonenylene group, group. Preferred alkenylene groups are C 2 -C 4 alkenylenes.

In formula I, n is 1 or 2, then 2 or 4 -CH ₂ groups are present in the ring that is fused with the benzene ring so that the ring is either 5-membered or 1-membered.

The group Ar in formula II in which R ⁸ is -NHR ¹⁸ and -NHR ¹⁸ and R ⁹ together represent a 5-membered or

A 6-membered heterocyclic ring may be, for example, a group in which Y is a carbon atom, R ⁸ is -NHR ¹³ and -NHR ^{1 =} together with R ⁹ represent a group of the formula -NH-CO-R ²³ , where R ²³ is an alkylene group, an alkenylene group or an alkyleneoxy group, a group of the formula -NH-SO ₂ -R ²⁴ , wherein R ²⁴ is an alkyleneoxy group, a group of the formula -NH-R ' ⁵ (COOR ² °), wherein R ^4,5 is an alkylene group or an alkenylene group and R ²⁶ is an alkyl group, or a group of the formula -NH-CO-NH- or -NH-CO-S-,

R ¹⁰ is -OR ¹ ', wherein R ¹⁹ is as defined above, alkyleneoxy

X is an alkyl group, p is 1, q is 1, and r is 0 or 1.

Alkylene groups, alkenylene groups and groups preferably contain 1 to 4 carbon atoms.

Preferred groups Ar of formula II in which R ⁸ is -NHR ¹⁸ and -NHR ^'8 and R ⁹ together form a 5-membered or 6-membered heterocyclic rings include groups in which Y is carbon, ^R8 is -NHR ¹⁸ and -NHR ¹⁸ and R ^? together a group of formulas -NH-CO-C (R ²⁷ ) = C (R ²⁸ ) - or or -NH-CO-CH 2 - or -NH-SO ₂ -CH ₂ -O- or

NH-C (COOR ²⁶ ) = CH- or -NH-CO-NH- or -NH-CO-S-, wherein the substituents R ²⁷ and R ²⁸ are independent of each other and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms and represent NH-CO-CH 2 -OR ²⁶ is an alkyl group having 1 to 4 carbon atoms, R ¹⁰ is a hydroxyl group, X is an alkyl group having 1 to 4 carbon atoms, p is 1, q is 1 and is 0 or 1.

An even more preferred Ar group of formula II are those wherein R ⁸ is -NHR ¹⁸ and wherein -NHR ¹⁸ and R 'together represent a 5-membered or 6-membered heterocyclic ring of formulas III, IIIa, IV, v, vi and v11

wherein R ²⁵ , R ³⁰ and R ³¹ are independently hydrogen or C 1 -C 4 alkyl,

Ο

wherein Z is an oxygen atom, an -NH- group or a sulfur atom.

The group Ar of formula II in which R ⁸ is a halogen atom and R 'is a hydrogen atom may be, for example, a group of formula II in which Y is a carbon atom, R ⁸ is a halogen atom, preferably a chlorine atom, R ⁹ is a hydrogen atom , R ¹⁰ is -NHR ¹⁸ , where R ¹⁸ is hydrogen or C 1-4 alkyl, preferably hydrogen or methyl, X is halogen or halomethyl, preferably chlorine or trifluoromethyl and p, q and r are in In all cases 1. Of these groups, Ar groups of formulas VIII and IX are preferred.

(IX) (IX)

As the Ar group of formula II in which R ⁸ is -OR ¹³ and R ⁹ is hydrogen, for example, a group of formula II in which Y is a carbon atom, R ⁸ is -OR ¹³ in which R ¹³ is an atom hydrogen, alkyl of 1 to 4 carbon atoms, alkoxyalkyl of 1 to 4 carbon atoms in each alkyl group, -COR ^'4 wherein R ¹⁴ is alkyl of 1 to 4 carbon atoms, aryl of 6 to 10 carbon or -N (R ¹⁵ ) R ¹⁶ wherein R ¹⁵ and R ¹⁶ are each independently hydrogen or C 1 -C 4 alkyl, R 10 is OR ¹⁹ or -NHR ¹⁹ wherein R ¹⁹ is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxyalkyl in each of the alkyls, or -COR ²⁰ wherein R ²⁰ is -N (R ²¹ ) R ²² , C 1 -C 4 alkyl; (C 4 -C 4), (C 1 -C 4) alkoxyalkyl, or (C 1 -C 4) -aryl C 6 to C 10 and R ²¹ , and R ²² are each independently hydrogen or C 1 -C 4 alkyl, each being 1 and n is zero. Preferred Ar groups are those of formula X and XI.

CH

As a group Ar of formula II in which ^R8 is -CHjCR ^ ³ may be a group of formula II, wherein Y is carbon, ^R8 is -CH, OR ^13, wherein R is H, alkyl of 1 to 4 carbon atoms, alkoxyalkyl of 1 to 4 carbon atoms in each C, ^R? is hydrogen, R ¹⁰ is -OR ' ^S , where R ¹⁹ is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxyalkyl in each of the alkyls or R ¹⁰ is -NHR ⁹ , wherein R ¹⁹ is hydrogen, C 1 -C 4 alkyl or -COR ²⁰ wherein R 0 is C 1 -C 4 alkyl, C 6 -C 10 aryl or -N (R ²¹ ) R ²² , wherein R ²¹ and R ²² are independently hydrogen or C 1 -C 4 alkyl, in each case 1 and r are zero, or a group of formula II wherein Y is nitrogen, R ⁸ is -CH; OR ¹³ where R is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxyalkyl in each alkyl, R ¹⁰ is -OR ¹⁹ wherein R ¹⁹ is hydrogen , (C 1 -C 4) alkyl or (C 1 -C 4) alkoxyalkyl in each from alkyl, par are zero and q is 1, with Ar being preferred groups of formulas XII, XIII and XIV.

(XII) (XIII) XIV

As Ar groups of formula II wherein R ³ is -NHR ¹³ , for example, groups of formula II wherein Y is carbon, R ³ is -NHR ^1J where R ¹³ is hydrogen, alkyl with C 1 -C 10 alkyl, C 1 -C 10 alkyl is interrupted. 1-3 heteroatoms, -COR ¹⁴ where R ¹⁴ is hydrogen, C 1 -C 10 alkyl or C 1 -C 10 alkyl interrupted by 1 to 3 heteroatoms, or R ¹³ is -C (= NH) ) R ¹ ', -SOR ¹⁷ or -SO 2 R ₁₇ , wherein R ₁₇ is C 1 -C 10 alkyl or C 1 -C 10 alkyl interrupted by 1 to 3 heteroatoms, R ₉ is hydrogen, R ₁₀ is hydrogen -OR ^18, wherein R ⁱ⁸ is H, alkyl of 1 to 4 carbon atoms or alkoxyalkyl having 1 to 4 carbon atoms in each C, p and q are both 1 and r is 0, the preferred values of Ar is a group of formula XV,

- R13

in particular those groups in which R ¹³ is hydrogen, C 1 -C 4 alkyl, -COR ¹⁴ wherein R ¹⁴ is hydrogen or C 1 -C 4 alkyl or R ¹³ is -SO ₂ R ¹³ wherein R ¹³ is C 1 -C 4 alkyl.

Particularly preferred Ar groups are those of formula III, IV, V, VII and XV as defined above.

The group R ¹ in formula I, may be a hydrogen atom, a hydroxyl group or a aikoxylová of 1 to 4 carbon atoms, such as methoxy, ethoxy, isopropoxy, n-butoxy or tert-butoxy, R ¹ is preferably a hydroxyl group.

In the case where R ¹ is a hydroxyl group or an alkoxy group, the carbon atom of the general formula (I) marked with an asterisk * preferably has the R configuration.

The groups Ŕ ² and R ³ in the compound of formula (I ') may, for example, independently of one another be a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, such as a methyl group or an ethyl group. In a most preferred embodiment, R ¹ is H and R ^J is hydrogen or methyl.

The groups R ⁴ , R ⁵ , R 0 and R 'in a compound of formula I may, for example, independently of one another be hydrogen, chlorine, fluorine, chloromethyl, trifluoromethyl, hydroxyl, alkoxy of 1 to 10 carbon atoms , (C 1 -C 10) alkyl, (C 1 -C 10) alkyl interrupted by one or more oxygen or sulfur atoms, or by one or more -NH-, -SO-, or -SO ₂ -, alkenyl; 2 to 4 carbon atoms, trimetyisilylová, triethylsilyl, phenyl, carboxy, alkoxycarbonyl C 1 -C 4 alkyl, -CONR ⁿ R ¹² (wherein R ¹¹ and R ¹² are independently H or alkyl of 1 to 4 carbon atoms), or R ⁴ and R ^5, R ⁵ and R ⁶ or R ⁶ and R ^7, together with the carbon to which they are attached may represent 5-membered or 6-membered carbocyclic ring which is preferably a cycloaliphatic ring which is preferably saturated, or a 5- or 6-membered oxygen-containing heterocyclic ring which contains one or two oxygen atoms. The substituents R ⁴ , R ⁵ , R ⁶ and R ⁷ are preferably hydrogen atoms or are such that the benzene ring to which they are attached is symmetrically substituted, for example, or (a) R ⁴ and R ⁷ are identical and R ⁵ and R 7 ⁶ are identical or together represent a symmetric ring, or (b) R ⁴ and R ⁵ together and R ⁶ and R ⁷ together represent identical rings. Even more preferred are compounds wherein R ⁴ and R ⁷ are identical substituents, namely a hydrogen atom, a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group, or R 0 and R 0 are identical substituents, namely a hydrogen atom , (C1-C4) -alkyl, (C1-C4) -alkoxy or (C1-C4) -alkoxyalkyl in each alkyl, or R ^; and R c together represent - (CH ₂ ) _S - or -O (O 3) 10 -, wherein s is 3 or i and i is 1 or 2.

Particularly preferred compounds of the present invention are those compounds of formula I wherein Ar is a group of formula III, IV, V, XII or XV, R ¹ is a hydroxyl group, R ² and R ³ are hydrogen and R ⁴ and R 'are identical substituents such as a hydrogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group, or R and R are identical substituents and are a hydrogen atom, a C1-C4 alkyl group, a C1-alkoxy group or R ⁵ and R ^c together represent - (CH ₂ ) ₄ - or -O (CH ₂ ) ₂ O- in the free moiety; in the form or in the form of a salt or in the form of a solvate. In those compounds in which the carbon atom of formula I is marked with an asterisk *, these are preferably of the R configuration. The most preferred compounds are those described in the following examples.

The compounds of formula (I) are capable of forming acid addition salts, particularly pharmaceutically useful acid addition salts. Pharmaceutically useful acid addition salts of the compounds of formula I include salts with inorganic acids, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, or with nitric acid, sulfuric acid, phosphoric acid and organic acids such as formic acid. , acetic acid, propionic acid, butanoic acid, benzoic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, p-chlorobenzoic acid, diphenylacetic acid, triphenylacetic acid, 1-hydroxynaphthalene-2-carboxylic acid, 3-hydroxynaphthalene- 2-carboxylic acid, with aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid, malic acid, with dicarboxylic acids such as fumaric acid, maleic acid or succinic acid and with sulfonic acids such as acid methanesulfonic acid or benzenesulfonic acid. These salts can be prepared from compounds of formula I by known salt-forming procedures.

Preferred solvates are pharmaceutically acceptable solvates, preferably hydrates.

The present invention also relates to a process for the preparation of compounds of formula I in free form, in the form of salts or in the form of solvates. The compounds may be prepared by a process comprising:

for the preparation of a compound wherein R ¹ is a hydroxyl group, or (i) reacting a compound of formula XVI / (XVI)

A r ¹ -C HC H ² R ² with a compound of formula XVII

(XVII) wherein Ar ¹ and Ar are as defined above, optionally in protected form, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are as defined above, and R ³² is a hydrogen atom or a protecting group or (ii) reducing the compound of Formula XVIII

wherein Ar ¹ , R ² , R ³ , R ⁴ , R ⁰ , R ^{6 by} carrying out said keto group and R ⁷ are as defined for -CH (OH) - or above, (a) for the preparation of a compound wherein R ¹ is a hydrogen atom, a reduction of the corresponding compound of formula I wherein R ¹ is a hydroxyl group, or (b) for the preparation of a compound of formula I wherein R ¹ is an alkoxy group, or (i) O-alkylation of a corresponding compound of formula I wherein R ¹ is a hydroxyl group, or (ii) reacting a corresponding compound of formula I having a leaving group instead of R ¹ with an alcohol of formula R ¹ H, where R ¹ is an alkoxy group, and

vzni knuta compound of of formula I protected form with possibly form, and transfers to the corresponding compound in n echránenej resulting compound of of formula I is isolated in free form, salt form or form solvate

Process (a) (i) may be carried out using known procedures for epoxide-amine reactions. It is preferably carried out without a solvent or in an inert solvent, for example in a hydrocarbon such as toluene or in an alcohol such as n-butanol. The reaction temperature is usually from 25 ° C to 200 ° C, preferably from 80 ° C to 150 ° C. Heating is performed either by a conventional method or by using microwave heating.

The process of variant (a) (ii) may be carried out by conventional methods, for example by reaction with sodium borohydride under conventional conditions.

The process of variant (b) is carried out according to known procedures used for the reduction of secondary alcohols to hydrocarbons. The process of variant (c) (i) may be carried out using known O-alkylation procedures, for example by reaction with an alkylating agent, such as alkyl halides, under known conditions. Process variant (c) (ii) may be carried out by conventional methods for cleaving benzyl groups, wherein the leaving group is, for example, a tosylate group, a mesylate group, a halogen atom or a hydroxyl group.

The compounds of the invention can be isolated and purified from the reaction mixture by conventional means. Isomers such as enantiomers may be obtained in conventional manner, for example, by fractional crystallization or asymmetric synthesis, from the corresponding asymmetrically substituted, for example, optically active starting materials.

Compounds of formula XVI are known or can be prepared by analogous known compounds, for example Medicinal Chemistry 1987, 30, of formula XVI in which the atom is chiral, can be prepared from

Ar ¹ —CH — Cl I I. OH R <

the procedures used to prepare the procedures described in Journal of 1563-1566. Compounds of general carbon marked with an asterisk * are compounds of formula XIX ¹ L (XIX) wherein Ar ¹ and R ² are as defined above and L is a leaving atom or group as described in WO 95/25104.

Alternatively, compounds of formula XVI may be prepared by epoxidation of compounds of formula XX

Ar ¹ -CH = CH-R ^: (XX) wherein Ar ¹ and R 2 are as previously defined, using commonly known methods, such as those described in the Examples below.

Compounds of formula XX are known or may be prepared by methods analogous to those used to prepare known compounds, for example those used in the following examples.

Compounds of formula (XVII) are known or can be prepared by procedures analogous to those used to prepare known compounds. The substituent R ³² as the amino protecting group of formula XVII may be a known group, for example as described in TW Greeen, PGM Wuts, Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons Inc, 1991, such as preferably benzyl or trifluoroacetyl. .

The compounds of formula XVII, wherein R ³ is H, for example, be prepared by reducing an oxime of the formula XXI

wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are as defined above. The reduction can be carried out by conventional methods used to reduce oximes to amines. For example, the reduction can be carried out by catalytic hydrogenation, preferably using palladium on carbon as a catalyst. Hydrogenation can be carried out using commonly known procedures, for example as described in RD Sindelar et al., J. Med. Chem., 1982, 25 (7): 858-864. The oximes of formula XXI can be prepared by the procedure described by RD Sindelar et al., Citation before, or analogous procedures.

Compounds of formula XVII in which R ⁴ and R ⁷ are hydrogen atoms may be prepared by reaction of a compound of formula XXII

R ³

R ³² -NH

(CH ₂ ) _n —CH 2 CH (XXII) '(CH ₂ ) _n —CH 2 CH with a compound of formula XXIII

R ^{5 -} C = C - R ⁵ (XXIII) wherein R ³ , R ⁵ , R ⁵ , R ³² and n are as previously defined. The reaction may be carried out in the presence of a catalyst such as tris- (triphenylphosphine) rhodium chloride. The reaction temperature can be, for example, from 60 ° C to 120 ° C. The reaction is preferably carried out in an inert solvent, for example ethanol, preferably at a temperature around the boiling point of the solvent. The reaction may be carried out using known procedures such as those described in WO 96/23760. If R ⁵ and R 0 are trialkylsilyl groups, then the reaction between compounds XXII and XXIII can be carried out in the presence of a metalcarbonyl complex catalyst, for example using the procedure described in KPC Vollhardt and R. Hillard, J. Am. Chem. Soc. 1977, 99 (12), 4058 or a method analogous thereto. Compounds of formula (XXII) may be prepared by the method described in WO 96/23760 or by analogous procedures. Compounds of formula XXIII are known or can be prepared by known methods.

Compounds of formula (XVII) wherein R ³ is alkyl, especially methyl, and n is 1 can be prepared by amination of the corresponding 2-alkylindan-one using ammonia and potassium ferrocyanide, for example, according to Fornum and Carlson, Synthesis, 1972, 191.

The compounds of formula XVII, as defined above, wherein R ^4, R ^5, R ⁶ and R ⁷ are arranged such that the benzene ring is substituted symmetrically excluding compounds in which R ^4, R ^5, R ^e, R ^7, and R ³⁰ are hydrogen atoms in which R ⁴ and R ⁷ are methyl or methoxy when R ⁵ , R ⁵ and R ³⁰ are hydrogen atoms in which R ⁴ , R ⁷ and R ³⁰ are hydrogen atoms when R ⁵ and R ⁶ are both hydroxyl, fluorine or chlorine. Particularly preferred intermediates of formula XVII are novel wherein (i) R ⁴ and R ⁷ are both hydrogen and R ⁵ and R ⁶ are C 2 -C 4 alkyl, C 2 -C 4 alkoxy , (C 1 -C 4) alkoxyalkyl in each of the alkyl moieties, or R ⁵ and R ⁶ together represent - (CH 2) S - or -O (CH 2) 10 - in which s is 1 to 4 and t is 1, or Or (ii) both R ⁴ and R ⁷ are C 2 -C 4 alkyl or C 2 -C 4 alkoxy and R ⁵ and R ⁶ are both hydrogen, C 1 -C 4 alkyl atoms, alkoxy of 1 to 4 carbon atoms and R ⁵ and R ^s are each hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or alkoxyalkyl having 1 to 4 carbon atoms in each from alkyl moieties or substituents R ⁵ and R ^c together represent -; CH 2) S ^- or -O (CH ₂ ) _c O ^- in which s is 1 to 4 and _t is 1 or 2.

Compounds of formula XVIII are novel compounds which can be prepared by reacting a compound of formula XXIV

Ar 1 CO-Hal (XXIV) wherein Ar ¹ is as defined above and Hal is a halogen atom, preferably a chlorine atom or a bromine atom, with a compound of formula XVII as defined above. The reactions can be carried out using conventional procedures, for example those described in Yoshizaki et al., J. Med. Chem. <197 6), 19 (9), 1138-42.

If desired, the protection of any reactive group can be carried out at any stage of the above procedures. The protecting groups used are those commonly known to those skilled in the art and can be introduced and removed using conventional procedures. For example, if the hydroxyl group in Ar ¹ is protected with a benzyl group, it can be removed by hydrogenation in the presence of palladium on carbon using conventional procedures such as those used in the examples below.

The compounds of formula I in free, salt or solvate form are useful as pharmaceuticals. Therefore, the invention also relates to compounds of formula I in free form, in salt form or in solvate form for use as medicaments. Compounds of formula I in free, salt or solvate form, hereinafter alternatively referred to as "compounds of the invention, have good β 2 -adrenoreceptor agonist activity. The β2 agonist activity, onset of action and duration of action of the compounds of the invention can be tested using guinea pig tracheal strips in an in vitro assay, according to the procedure of R.A. Coleman and A.T. Nials, J. Pharmacol. Methods 1989, 21 (1), 71-86. The binding ability and selectivity for β 2 -adrenoreceptor relative to β 2 -adrenoreceptor can be measured by the classical filtration binding assay according to the procedure of Current Protocols in Pharmacology (SJ Enna (ed. In chief) et al., John Wiley & Son, Inc, 1998) or cAMP in cells expressing β2- or β-adrenoreceptors, following the procedure of B. January et al., British J. Pharmacol., 1998, 123, 701-711.

The compounds of the invention normally have a rapid onset of action and have a prolonged stimulating effect on the β2-adrenoreceptor, the compounds of the examples given below which have Ki (β2) values of the order of 0.1 to 1000 nM. and have a binding selectivity for β2-3άβ ηο ^ οερίοτ relative to a β 2 -adrenoreceptor of from 1.5 to 500. For example, the compounds of Examples 1, 2, 4, 5, 8, 27 and 29 have β 2 and β 2 binding potency, measured as determination of cAMP in cells expressing β2- and βΐ-adre21 noreceptors, represented by EC50 single values (β2 / β1) (in nM) 0.92 / 9.52, 0.23 / 1.25, 6.07 / 14.5, 0.79 / 6.10, 0.3 / 3.60,

0.57 / 8.46 and 0.012 / 0.5. The compounds of Examples 2, 4, 5, 27 and have the following T (50%) times (in minutes)> 400 at 71 nM concentration, 82 'at 100 nM, 444 at 100 nM, 222 at 1.0 nM and 279 at 10 nM in a guinea pig tracheal strip assay, where T (50%) is the time to decrease the inhibitory concentration to 50% of its maximum height.

In view of the effect of the compounds of the invention as P2-aconists, the compounds of the invention are suitable for use in the treatment of any conditions which can be prevented or alleviated by activation of the P2-adrenoreceptor. Because of their long-term and selective β 2 -agonist effect, the compounds of the invention are useful in relaxing bromchial smooth muscle and relieving bronchoconstriction. Relief of bronchoconstriction can be measured in models such as the in vivo plethysmographic models reported by Chong et al., J. Pharmacol. Toxicol. Methods 1998, 39, 163-168; Hammelmann et al., Am. J. Respir. Crit. Čare Med., 1997, 156, 766-775 and analogous models. The compounds of the invention are therefore useful for the treatment of obstructive or inflammatory airway diseases. Due to their long-term effect, the compounds of the invention can be administered once daily for the treatment of these diseases. In another aspect, the compounds of the invention commonly exhibit characteristics indicating that they have a low incidence of side effects that are otherwise commonly associated with β 2 -agonists, such as tachycardia, chills, nervousness, and the compounds of the invention are therefore suitable for treating immediate need. (rescue) as well as for the prophylactic treatment of obstructive or inflammatory airway diseases.

Treatment of the diseases of the invention may be symptomatic or prophylactic. Inflammatory or obstructive airways diseases to which this invention is applicable include asthma of any type, origin including internal (non-allergic) asthma and external (allergic) asthma. Asthma treatment also includes treating subjects such as less than 4 to 5 years of age who show sipotic symptoms and who are diagnosed or diagnosed as a "sleeping baby" which is an established category of adult medical care patients who are now identified as early-onset or early-stage asthma. (For simplicity, this particular asthmatic condition is referred to as wheezy infant syndrome).

The prophylactic effect in the treatment of asthma is evident by reducing the frequency or severity of a symptomatic seizure, such as an acute asthma or bronchoconstrictor seizure, improving lung function, or improving airway hyperactivity. It may further be apparent by reducing the requirements for further, symptomatic therapy, for example, therapy intended to reduce or prevent a symptomatic seizure that has already occurred, for example with anti-inflammatory (e.g., corticosteroid) agents or bronchodilators. The benefit of prophylaxis in asthma is particularly evident in subjects prone to "morning greeting." Morning greeting is a recognized asthma syndrome, common to a significant percentage of asthmatics, characterized by an asthma attack, for example between 4 and 6 am, at a time that is normally substantially distant from any previously applied symptomatic asthma therapy.

Of other inflammatory. or obstructive airways diseases or conditions to which this invention is applicable may be named adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) or chronic obstructive airway disease (COAD), including or with chronic bronchitis. associated dyspnoea, emphysema, as well as exacerbation of airway hyperreactivity due to other drug therapy, especially other inhalation drug therapy. The invention is also applicable to the treatment of bronchitis of any type or origin, including, for example, acute, ara23 chidic, catarrhal, croupous, chronic or fitinoid (phtthinoid) bronchitis. Other inflammatory or obstructive airways diseases to which this invention is applicable include pneumoconiosis (inflammatory, commonly occupational, lung diseases often associated with airway obstruction, whether chronic or acute due to repeated respiration of dust) of any type or origin, including, for example, aluminosis , anthracosis, asbestosis, chalcose, ptilosis, siderosis, silicosis, tobacco and bysinosis.

Due to the action of the 32-agonist, the compounds of the invention are also useful in the treatment of conditions requiring relaxation of uterine smooth muscle or the vascular system. Thus, they are useful for preventing or relieving premature labor during pregnancy. They are also useful for the treatment of chronic and acute urticaria, psoriasis, allergic conjunctivitis, actinitis, hay fever and mastocytosis.

The compounds of the invention are also useful as co-therapeutic agents for use in conjunction with other anti-inflammatory agents or bronchodilators, particularly in the treatment of obstructive or inflammatory diseases of the respiratory tract, such as those mentioned above, for example as potentiators of the therapeutic effects of these drugs or as a means to reduce the required doses or to reduce the potential side effects of these drugs. The compounds of the invention may be mixed. With anti-inflammatory or bronchodilators in a single pharmaceutical composition, or both can be applied separately before, simultaneously with or after the application of the anti-inflammatory or bronchodilators. Such anti-inflammatory agents include steroids, particularly glucocorticosteroids such as budesonide, beclamethasone, fluticasone or mometasone, and dopamine receptor agonists such as cabergoline, bromocriptine or ropinirole. Such bronchodilators include anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxitropium bromide and tiotropium bromide. The combination of the compounds of the invention and steroids can be used, for example, for the treatment of COPD or especially asthma. Combinations of the compounds of the invention and anticholinergic or antimuscarinic agents or dopamine receptor agonists can be used, for example, for the treatment of asthma or, in particular, COPD.

Accordingly, the present invention also relates to a method for treating obstructive or inflammatory airways disease, which comprises administering to a subject, particularly a human subject, a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as described above. . According to another aspect, the invention relates to compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, as described above, for use in the preparation of a medicament for the treatment of obstructive or inflammatory airways diseases.

The compounds of the invention may be administered by any suitable means, i.e. orally, for example in the form of tablets or capsules, parenterally, for example intravenously, topically to the skin, for example psoriasis, intranasally, for example hay fever, or preferably by inhalation. obstructive or inflammatory airway diseases.

In another aspect, the invention also relates to pharmaceutical compositions which comprise a compound of formula I in free form or in the form of a pharmaceutically acceptable salt or solvate thereof, optionally together with a pharmaceutically acceptable diluent or carrier. These compositions can be prepared using conventional diluents or vehicles and techniques known to the art of galenium. Thus, oral dosage forms may include tablets and capsules. Formulations for topical application may be prepared in the form of creams, ointments, gels or transdermal delivery systems such as patches. Compositions for inhalation may contain aerosol or other nebulizer formulations or dry powder formulations.

The invention also encompasses (A) compounds of formula I as described above in free form or in the form of pharmaceutically acceptable salts or solvates thereof, in inhalable form, (B) an inhalable composition comprising these compounds in inhalable form together with a pharmaceutically usable carrier in an inhalable (C) a pharmaceutical composition comprising the compounds in inhalable form in association with an inhalation device, and (D) inhalation devices comprising the compounds in inhalable form.

The dosages used in the practice of the invention will, of course, vary and depend, for example, on the particular condition to be treated, the effect desired and the mode of administration. In general, a suitable daily dose for administration by inhalation is of the order of from 1 to 5000 pg.

The invention is illustrated by the following examples. The compounds used in the examples were prepared as follows:

DETAILED DESCRIPTION OF THE INVENTION

Intermediate 1: 5,6-Diethylinden-2-ylamine hydrochloride

Preparation 1: 3-Chloro-2- (3,4-diethylphenyl) -1-propanone

1,2-Diethylbenzene (10.9 g, 74.6 mmol) and propionyl chloride (9.7 g, 74.6 mmol) was added dropwise to a mixture of aluminum chloride (22.3 g, 167.8 mmol) in 30 min. nitromethane (75 mL). The reaction mixture is stirred for 2 hours at room temperature, then 70 g of ice and 14 ml of concentrated sulfuric acid are added. The aqueous phase is extracted with ether and the combined organic phases are extracted with 2N hydrochloric acid and saturated sodium chloride solution. The organic phase was further treated with activated carbon, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo.

1 H-NMR (CDCl ₃ ) ppm: 7.8 (1H, s, Ar), 7.7 (1H, d, Ar), 7.2 (IH, d,

Ar), 3.9 (2H, t, CH ₂ ), 3.4 (2H, t, CH ₂ ), 2.8 (4H, q, CH ₂ CH ₃ ), 1.2 (6H, m, CH ₃ ).

Preparation 2: 2,3-Dihydro-5,6-diethyl-1H-inden-1-one

3-Chloro-2- (3,4-diethylphenyl) -1-propanone (15.5 g) was dissolved in 66 ml of concentrated sulfuric acid and heated at 90 ° C for 4 hours. The reaction mixture was cooled, ice (70 g) was added and the aqueous solution was extracted twice with toluene. The organic phase is washed with sodium bicarbonate solution, saturated sodium chloride solution and purged with activated carbon and dried over magnesium sulfate. After filtration, the solvent was evaporated in vacuo. The product was purified by flash chromatography (silica gel, hexane / ethyl acetate 10: 1) followed by crystallization in hexane.

^1H-NMR (CDCl3) ppm: 7.6 (IH, s, Ar), 7.3 (IH, d, Ar), 3.1 (2H, m, _CH2), 2.7 (6H, m CH ₂ + CH ₂ CH ₃ ), 1.2 (6H, m, CH ₃ ).

Preparation 3: 5,6-Diethyl-3-oxime-1H-indene-1,2 (3H) -dione

2,3-Dihydro-5,6-diethyl-1H-inden-1-one (5 g, 26 mmol) in methanol (75 mL) was warmed to 40 ° C and n-butylnitride (3.0 g, Concentrated hydrochloric acid (1.25 ml) was then added. After one hour, the reaction mixture was cooled to room temperature, the precipitated product was filtered, washed with ice-cold methanol and dried.

^H-NMR (d6-DMSO) ppm: 12.6 (IH, s, OH); 7.4 (IH, s, Ar), 7.3 (IH, d, Ar), 3.6 (2H, s, CH ₂ ), 2.6 (4H, q, CH ₂ CH ₃ ), 1.1 (6H, m, CH ₃ ).

Preparation 4: 5,6-Diethylindan-2-ylamine hydrochloride

5,6-Diethyl-3-oxime-2H-indene-1,2 (3H) -dione (4.5 g) was added to a mixture of acetic acid (150 mL) and concentrated sulfuric acid (4.5 mL). 5% Palladium on carbon (1.5 g) was added and the reaction mixture was degassed with nitrogen and then hydrogenated for 5 hours.

The catalyst is filtered off, the pH is adjusted to 10 by addition of 4M sodium hydroxide and the solution is extracted with chloroform. The organic phase is dried over magnesium sulphate and the solvent is evaporated off under vacuum. The residue was redissolved in a minimum amount of ether and saturated ethereal hydrogen chloride was added. The white precipitate was filtered off and dried. 5,6-Diethylindan-2-ylamine hydrochloride, a compound of formula XVII wherein R ³ , R ⁴ and R ⁷ are hydrogen, R ⁵ and R ⁶ are both ethyl, R ³⁰ is hydrogen and is first

1 H-NMR (d 6 -DMSO) ppm: 8.7 (3H, bd s, NH ₃ ), 7.3 (2H, s, Ar), 4.2 (1H, bd s, CH), 3, Δ (2H, dd, CH ₂ ), 3.3 (2H, dd, CH ₂ ), 2.8 (4H, q, CH ₂ CH ₃ ), 1.4 (6H, t, CH ₃ ).

Other compounds of formula XVII are prepared by procedures analogous to those used for the preparation of Intermediate 1 or starting from available compounds and using procedures analogous to Preparation 3 and

4. These compounds of formula XVII are shown in the following table, wherein R ³ is in each case a hydrogen atom and n is 1.

intermediate product R ⁴ R ³ R ⁵ R ⁷ 2 CH ₃ CH ₂ H H 3 H - (CH ₂ ) 4 - H 4 H -O (CH ₂ ) ₂ o- T 7 n 5 H CH ₃ (CH ₂ ) ₃ CH ₃ (CH ₂ ) ₃ H 6 H CH; (CH ₂ ) 2 CH ₃ (CH ₂ ) ₂ H 7 H CH O ch ₃ o H

Intermediate 2: ES + MS m / e (MH &lt; ^{+ &gt;} ) = 204

Intermediate 3: ¹ H-NMR (d 6 -DMSO) ppm: 8.1 (3E, bd s, NH 2), 6.9 (2H, s, Ar), 3.9 (1H, bd s, CH) , 3.2 (2H, dd, _CH2), 2.8 (2H, dd, _CH), 2.7 (4H, m, _CH2 Ar), 1.7 (6H, t, _CH2).

Intermediate 4: ¹ H-NMR (d 6 -DMSO) ppm: 8.3 (3H, bd s, NH 3), 6.85 (2H, s, Ar), 4.2 (4H, s, 2CH ₂ ), 3.1 (2H, dd, _CH2), 2.85 (2H, dd, _CH2).

Intermediate 5: ^X H-NMR (d6-DMSO) ppm: 6.9 (2H, s, Ar), 3.8 (IH, m, CH), 3.1 (2H, dd, CHU, 2.6 ( 2H, dd, CHU, 2.5 (4H, t, 2CHJ, 1.65 (2H, bd s, NH _2), 1.55 (4H, m, 2CH _2), 1.4 (4H, m, 2CHJ 0.95 (6H, t, 2H).

Intermediate 6: ¹ H-NMR (d 6 -DMSO) ppm: 8.1 (3H, bd s, NH ₃ ), 7.0 (2H, s, Ar), 3.9 (1H, bd s, CH), 3.2 (2H, dd, CHU, 2.8 <2H, dd, CHU, 2.5 (4H, q, etch ₂ Ar), 1.6 (4H, q, CHU, 0.9 (6H, t , CH ₃ ).

Intermediate 7 1 H-NMR (d 6 -DMSO) ppm: 8.3 (3H, bd s, NHJ, 6.9 (2 H, s, H-Ar), 3.9 (IH, bd m, CHN), 3.7 (6H, s, CH ₃ O) 3.2 (2H, dd, CHJ, 2.9 ( 2H, dd, CH3. Intermediate 8: : 2- (Trifluoroacetylamino) -5,6-bis- (methoxymethyl) -1- indan

Following the procedure of Magnus et al., Tetrahedron Lett. 1993, 34,

23-26, a solution of commercially available 1,4-dimethoxy-2-butyne (1.32 g, 11.5 mmol) in nitrogen-degassed ethanol is heated to 80 ° C with stirring and under a nitrogen atmosphere. Then tris- (triphenylphosphine) rhodium chloride (64 mg, 0.07 mmol) was added and a solution of 2,2,2-trifluoro-N- [1- (2-propynyl) -3- butinyl] acetamide (470 mg, 2.32 mmol, prepared according to literature procedure: AG Romero, A. Jeffrey, PCT Int. Appl WO 9623760) in nitrogen-degassed ethanol (2 mL). The mixture was stirred under an atmosphere of nitrogen at 80 ° C for an additional 3 hours. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with hexane / ethyl acetate (2: 1).

^H-NMR (CDC1 ₃₎ ppm: 2.9 (2H, dd), 3.35 (2H, dd), 3.45 (6H, s),

4.57 (4H, s), 4.85 (1H, m), 6.4 (1H, br s), 7.30 (2H, s).

Intermediate 9: 2-Amino-5,6-bis- (methoxymethyl) indane

A solution of potassium hydroxide (150 mg, 2.60 mmol) in water (0.5 mL) was added to a solution of 2- (trifluoroacetylamino) -5,6-bis- (methoxymethyl) indane (240 mg, 0.75 mmol) in methanol (3 ml) and the mixture was heated to boiling for 2.5 hours. The solvent was evaporated in vacuo and the residue was partitioned between aqueous sodium hydroxide (10 mL) and ethyl acetate (20 mL). The organic extract was dried over magnesium sulfate and the solvent was evaporated in vacuo. Obtained as a darkly colored oil.

^X H-NMR (CDC1 ₃₎ ppm: 2.60 (2H, dd), 3.10 (2H, dd), 3.33 (6H, s),

3.75 (1H, m), 4.42 (4H, s), 7.17 (2H, s).

Intermediate 10: 8-Hydroxy-5 - [(indan-2-ylamino) acetyl] -1H-quinolin-2-one

5- (Chloroacetyl) -8-hydroxy-2 (1H) -quinolinone (25 mg,

0.105 mmol) prepared according to the literature procedure (Yoshizaki, Shiro, et al., J. Med. Chem., 1976, 19 (9), 1138-1142) was reacted with undiluted indan-2-ylamine (205 mg, 1 mg). The reaction mixture was purified by flash chromatography (silica gel, dichloromethane / methanol 9: 1) ES + MS m / e = 335 (MH).

Intermediate 11:

The compound of formula XVIII wherein Ar is a group of formula III, R ²⁷ , R ²⁸ and R ²⁹ are hydrogen, R ² , R ³ , R ⁴ and R ⁷ are hydrogen and both R ⁵ and R 0 are methoxy groups, prepared analogously to the procedure described for the preparation of Intermediate 10. ES + MS m / e = 395 (MH +).

Intermediate 12: 8-Benzyloxy-3-methyl-5-oxiranyl-2H-quinolin-2-one

8-Hydroxy-3-methyl-2H-quinolin-2-one was prepared according to the procedure of Wang et al. (T.C. Wang, Y. L. Chen,

K. H. Lee, C.C. Izeng Synthesis 1997, 87-90).

1 H-NMR (d 4 -CH ₃ OH) ppm: 2.14 (3H, s), 6.84-6.89 (1H, m), 6.95-7.03 (2H, m), 6.9 (1H, s), 7.71 (1H, s).

8-Benzyloxy-3-methyl-2H-quinolin-2-one

To a suspension of potassium carbonate (2.98 g) in a solution of 8-hydroxy-3-methyl-1H-quinolin-2-one (1.26 g) in acetone (36 mL) was added benzyl bromide (1.28 mL) at room temperature. The reaction mixture was heated under reflux for 18 hours, filtered, evaporated and the residue purified by flash chromatography on silica gel, eluting with 2% methanol in dichloromethane.

¹ H-NMR (CDCl ₃ ) ppm: 2.11 (3H, s), 5.13 (2H, s), 6.92-6.98 (1H, m), 7.02-7.08 (2H , m), 7.29-7.40 (5H, m), 7.57 (1H, s), 9.23 (1H, s).

8-Benzyloxy-5-bromo-3-methyl-1H-quinolin-2-one

A solution of bromine (0.57 g) in acetic acid (2 mL) was added dropwise at room temperature to a solution of 8-benzyloxy-3-methyl-2H-quinolin-2-one (0.94 g) and sodium acetate (0.96). g) in acetic acid (12 mL). The reaction mixture was stirred at room temperature for 3 hours, evaporated and the residue partitioned between water (5 ml) and ethyl acetate (5 ml) and extracted twice more with ethyl acetate (5 ml). The combined organic extracts were dried over magnesium sulfate and purified by flash chromatography on silica gel, eluting with 2% methanol in dichloromethane.

1 H NMR (CDCl 3) ppm: 2.27 (3H, s), 5.18 (2H, s), 6.83 (1H, d),

7.39 (1H, d), 7.37-7.41 (5H, m), 7.91 (1H, s), 9.08 (1H, s).

8-Benzyloxy-3-methyl-5-vinyl-2H-quinolin-2-one

Palladium tetrakis (triphenylphosphine) (30 mg) was added at room temperature to a solution of 8-benzyloxy-5-bromo-3-methyl-2H31

-quinolin-2-one (239 mg) and tributylvinyl tin (203 μΐ) in toluene (7 mL). The reaction mixture was then heated at 100 ° C for 2 hours, cooled to room temperature, evaporated and the residue purified by flash column chromatography on silica gel eluting with 2% ethyl acetate in dichloromethane.

@ 1 H-NMR (CDCl3) ppm: 2.24 (3H, s), 5.18 (2H, s), 5.32-5.39 (1H, m), 5.61-5.68 (IH, m), 6, 95 (IH, d) , 7.09-7.20 (1H, m), 7.21-7.26 (2 H, m), 7.31-7.43 (4H, m) 7.89 (1H, s), 9.20

(1 H, s).

8-Benzyloxy-3-methyl-5-oxiranyl-2H-quinolin-2-one

To 8-benzyloxy-3-methyl-5-vinyl-1H-quinolin-2-one (300 mg) was added a 0.1 M solution of dimethyldioxirane in acetone (12.4 mL). After stirring at room temperature for 2 hours, evaporation of the solvent in vacuo gave the desired product.

¹ H-NMR (CDCl ₃ ) ppm: 2.23 (3H, s), 2.77-2.81 (1H, m), 3.13-3.23 (IH, m), 4.17-4 21 (1H, m), 5.18 (2H, s), 6.91 (IH, d), 7.01 (IH, d), 7.93 (IH, s), 9.10 (IH, with).

Intermediate 13: 8-Benzyloxy-5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -3-methyl-2H-quinolin-2-one

A solution of Intermediate 12 (65 mg) and 5,6-diethylindan-2-ylamine (120 mg) in dimethylsulfoxide (1.5 mL) was heated at 90 ° C for 18 h. The solvent was evaporated in vacuo and the product was purified by flash chromatography on silica gel eluting with 10% methanol in dichloromethane.

ⁿ C-NMR (d 4 -CH ₃ OH) ppm: 15.96; 17.14; 26.33; 36.77; 53.34; 59.82; 67.33; 71.73; 112.09; 118.98; 121.73; 125.42; 128.74; 129.24; 129.47; 129.61; 131.84; 134.56; 137.52; 137.64; 142.29; 145.94; 164.02.

Intermediate 14: 8-Methoxymethoxy-6-methyl-5-oxiranyl-2H-quinolin-2-one

8-Hydroxy-6-methyl-1H-quinolin-2-one was prepared according to the procedure of Wang et al. (T. C. Wang, Y. L. Chen, K. H. Lee, C. C. Izeng, Synthesis 1997, 87-90).

1 H-NMR (d 6 -DMSO) ppm: 2.26 (3H, s), 6.45 (1H, d), 6.79 (1H, s),

6.90 (1H, s); 7.78 (1H, s).

5-Bromo-8-hydroxy-6-methyl-2B-quinolin-2-one% solution of hydrobromic acid in acetic acid (324 μΐ) is added dropwise at room temperature to a solution of 8-hydroxy-6-methyl-1H-quinolin-2-one (316 mg) in dimethylsulfoxide (9 mL). The reaction mixture was allowed to stand for 18 hours at room temperature, then the solvent was evaporated in vacuo.

¹ H-NMR (d 6 -DMSO) ppm: 2.33 (3H, s), 6.58 (1H, d), 6.92 (IH, s), 8.03 (IH, d), 10.44 (1H, s), 10.67 (1H, br s).

5-Bromo-8-methoxymethoxy-6-methyl-2H-quinolin-2-one

Methoxymethyl chloride (410 μΐ) was added at 0 ° C to a suspension of potassium carbonate (1.24 g) in a solution of 5-bromo-8-hydroxy-6-methyl-2H-quinolin-2-one (480 mg) in dimethylformamide ( 9 ml). The reaction mixture was stirred at room temperature for 18 hours, filtered, the solvent was evaporated in vacuo and the product purified by flash column chromatography on silica gel eluting with 2% methanol in dichloromethane.

¹³ C-NMR (CDCl ₃ ) ppm: 23, 42; 56.52; 95.07; 115.78; 116.19; 119.32; 123.30; 128.13; 132.14; 139.78; 141,78; 161.32.

8-methoxymethoxy-6-methyl-5-vinyl-2H-quinolin-2-one

Palladium (II) bis (triphenylphosphine) chloride (98 mg) was added at room temperature to a solution of 5-bromo-8-methoxymethoxy-6-methyl-2H-quinolin-2-one (410 mg) and tributylvinyltin (603 μΐ) in dimethylformamide ( 14 ml). The reaction mixture is heated at room temperature for 24 hours

90 ° C, followed by evaporate and evaporate is being cleaned f lash Chromaticity column chromatography eluting with silica gel 2% methanol in dichloromethane. ¹ H-NMR (CDCl ₃ ) ppm: 2.19 (3H, s), 3.41 (3H, s) 5.18 (1K, d), 5.20 (2H, s), 5.60 (IH, d), 6.52 (IH, d), 6,63- 6, 69 (IH, m)

6.96 (1H, s), 7.95 (1H, d), 9.78.

8-methoxymethoxy-6-methyl-5-oxiranyl-2H-quinolin-2-one

Prepared from 8-methoxymethoxy-6-methyl-5-vinyl-1H-quinolin-2-one (186 mg) by the procedure of the last step of Preparation of Intermediate 12.

¹ H-NMR (CDCl3) ppm: 2.38 (3H, s); 2.68-2.72 (IH, m), 3.19-3.23 (IH, m) , 3.43 (3H, s), 3.97-4.01 (1H, m), 5.21 (2H, s) 6.60 (IH, d) , 6.98 1 (LH, s), 8.22 (lH, d) , 9.09 (1H, s).

Intermediate 15: (R) -2- (4-Benzyloxy-3-nitrophenyl) oxirane was prepared according to the procedure of R. Hett et al., Tetrahedron Lett. 1997, 38 (7), 1125-1128.

Intermediate 16: (S) -8-Benzyioxy-5-oxiranyl-2H-quinolin-2-one

8-Benzyloxy-5 - [(S) -2-chloro-1-hydroxyethyl] -2 H -quinolin-2-one.

(S) -2-methyl-CBS-oxaazaborolidine IM in toluene (0.30 mL, 0.30 mmol) was added to anhydrous tetrahydrofuran (10 mL) in an oven-dried flask. The borane-tetrahydrofuran IM complex in tetrahydrofuran (3.05 mL) was then added dropwise and the solution was stirred for 15 minutes at room temperature and then cooled to 0 ° C. Then, 8-benzyloxy-5-chloroacetyl-2 H -quinolin-2-one (100 g) prepared according to WO 95/25104 is added in small portions over 30 minutes. The reaction mixture was then stirred at 0 ° C. The reaction was complete by TLC (thin layer chromatography) in 15 minutes. The reaction was quenched by the addition of methanol (1 mL), the solvents were removed in vacuo and the residue partitioned between 0.2 M sulfuric acid (100 mL) and chloroform (10 mL). The organic phase is dried over magnesium sulphate and the solvent is removed in vacuo and the product is crystallized from ethyl acetate. TLC (silica gel, dichloromethane / methanol 25: 1 Rf = 0.30).

(S) -8-Benzyloxy-5-oxiranyl-2H-quinolin-2-one

8-Benzyloxy-5 - [(S) -2-chloro-1-hydroxyethyl] -22H-quinolin-2-one (0.55 g) was dissolved in acetone (20 mL). Potassium carbonate (0.58 g) was added and the reaction mixture was heated to reflux. TLC indicated complete reaction after 18 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase is dried over magnesium sulphate and the solvent is evaporated off under vacuum. The product is ground in diethyl ether, filtered off and dried. TLC (silica gel, dichloromethane / methanol 25: 1 Rf = 0.45).

Intermediate 17: 6,7,8,9-Tetrahydro-5H-benzocyclohepten-7-ylamine

Benzyl- (6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl) -amine

5, 6, 8,9-Tetrahydrobenzocyclohepten-7-one (3.00 g), and benzylamine (2.00 g) were dissolved in ethanol (50 mL). A catalytic amount of 10% palladium on carbon was added and the reaction mixture was stirred under a hydrogen atmosphere at room temperature. TLC indicated complete reaction after 24 hours. The catalyst was filtered off and the solvent was evaporated in vacuo. The product is not further purified. TLC (silica gel, hexane / ethyl acetate 1: 2 Rf = 0.50).

6,7,8,9-Tetrahydro-5H-benzocyclohepten-7-ylamine

Benzyl- (6,7,8,9-tetrahydro-5 H -benzocyclohepten-7-yl) amine (2.80 g) was dissolved in methanol (100 mL) and the protecting group was removed by adding a catalytic amount of 10% palladium on coal and hydrogenation in a hydrogen atmosphere. TLC indicated that the reaction was complete in 24 hours. The catalyst was filtered off and the solvent was removed in vacuo. The product is not further purified. TLC (silica gel, dichloromethane / methanol 25: 1 Rf = 0.15).

Intermediate 18: Benzyl- (5,6-diethylindan-2-yl) amine

N- (5,6-Diethylindan-2-yl) benzamide

5,6-Diethylindan-2-ylamine (4.10 g) was dissolved in dichloromethane (150 mL) and triethylamine (2.41 g) was added. Benzoyl chloride (3.20 g) was then added dropwise and the reaction mixture was stirred at room temperature. According to TLC, the reaction was complete in 1 hour. The solution was washed with 0.2 M hydrochloric acid solution (100 mL), water (100 mL) and brine (100 mL). The organic phase is dried over magnesium sulphate, filtered and the solvent is evaporated off under vacuum. The product crystallizes from ethyl acetate. TLC (silica gel, dichloromethane / methanol 10: 1 Rf = 0.85).

Benzyl- (5,6-diethyl-indan-2-yl) -amine

N- (5,6-Diethylindan-2-yl) benzamide (3.30 g) was dissolved in anhydrous tetrahydrofuran (100 mL) and then added dropwise. solution of 1 M lithium aluminum hydride in tetrahydrofuran (22.52 mL). The reaction mixture was stirred at 50 ° C. TLC indicated that the reaction was complete after 6 hours. The reaction mixture was allowed to cool and poured slowly into a mixture of ice and water (200 mL) and extracted with diethyl ether (2 x 150 mL). The organic phase is dried over magnesium sulphate, filtered and the solvent is evaporated off under vacuum. The product is not further purified. TLC (silica gel, hexane / ethyl acetate 2: 1 Rf = 0.20).

Intermediate 19: (R) -1- (3-Amino-4-benzyloxyphenyl) -2- [benzyl (5,636)

(diethylindan-2-yl) amino] ethanol (R) -2- [Benzyl- (5,6-diethylindan-2-yl) amino] -1- (4-benzyloxy-3-nitrophenyl) ethanol

The title compound was prepared from Intermediate 15 (3.01 g) and Intermediate 18 (3.10 g) by a method analogous to that used in the preparation of (S) -benzyloxy-5- [2- (5,6-diethylindane-). 2-ylamino) -1-hydroxyethyl] -1H-quinolin-2-one in Example 19. TLC indicated that the reaction was complete after 24 hours. The product was purified by flash column chromatography on silica gel eluting with n-hexane: ethyl acetate 4: 1. TLC (silica gel, hexane / ethyl acetate 4: 1 Rf = 0.25).

(R) -1- (3-Amino-4-benzyloxyphenyl) -2- [benzyl- (5,6-diethylindan-2-y)

1) amino] ethanol (R) -2- [Benzyl- (5,6-diethylindan-2-yl) amino] -1- (4-benzyloxy-3-nitrophenyl) ethanol (3.00 g) is dissolved in tetrahydrofuran (50 mL) and toluene (50 mL). A catalytic amount of platinum oxide is added and the solution is stirred under an atmosphere of hydrogen. TLC indicated that the reaction was complete after 6 hours. The catalyst was filtered off and the solvent was evaporated in vacuo. The product is not further purified. TLC (silica gel, n-hexane / ethyl acetate 1: 1 Rf = 0.75).

Intermediate 20: 1- (3-Amino-4-benzyloxyphenyl) -2- [benzyl- (5,6-diethylindan-2-yl) amino] ethanone

2- [Benzyl- (5,6-diethylindan-2-yl) amino] -1- (4-benzyloxy-3-nitrophenyl) ethanone

1- (4-Benzyloxy-3-nitrophenyl) -2-bromoethanone (2.00 g) according to the procedure of R. Hett et al., Tetrahedron Lett. (1997) 38 (7)

1125-1128) was dissolved in dimethyl ketone (100 mL). Triethylamine (0.64 g) was added followed by benzyl- (5,6-diethylindan-2-yl) amine (1.60 mL). The reaction mixture is then heated to reflux. According to TLC, the reaction was complete after 3 hours.

The solvent was evaporated in vacuo and the product purified by chromatography (silica gel, n-hexane / ethyl acetate 4: 1) (silica gel, n-hexane / ethyl acetate 2: 1 Rf = 0.75).

flash

TLC

1- (3-Amino-4-benzyloxyphenyl) -2- [benzyl- (5,6-diethylindan-2-yl) amino] ethanone

The title compound was prepared from 2- [benzyl- (5,6-diethylindan-2-yl) amino] -1- (4-benzyloxy-3-nitrophenyl) ethanone (1.50 g) according to the procedure described for the preparation of (Rj). The 1- (3-amino-4-benzyloxyphenyl) -2- [benzyl- (5,6-diethylindan-2-yl) amino] ethanol in Example 19. TLC indicated the reaction was complete in 48 hours. The product was purified by flash column chromatography (silica gel, n-hexane / ethyl acetate 4: 1), TLC (silica gel, n-hexane / ethyl acetate 2: 1 Rf = 0.70).

¹ H NMR (CDCl ₃ , 400 MHz) ppm:

2.60 (4H, g); 3.00 (4H, m);

1.20 (6H, t), 1.60 (2H, broad),

3.90 (6H, m), 5.15 (2H, s), 6.80 (1H, d), 6.95 (2H, s), 7.30 (12H, m).

Intermediate 21: Benzyl- (4,5,6,7-tetramethylindan-2-yl) amine

3-Chloro-1- (2,3,4,5-tetramethyl-phenyl) -propan-1-one

The title compound was prepared from 1,2,3,4-tetramethylbenzene and 3-chloropropionyl chloride according to the procedure of Preparation

First

¹ H NMR (CD 3 OD) ppm: 7.50 (1H, s), 4.20 (2H, t), 3.60 (2H, t),

2.60 (3H, s), 2.57 (3H, s), 2.52 (3H, s), 2.50 (3H, s).

4,5,6,7-Tetrametvlindan-l-one

The title compound was prepared from 3-chloro-1- (2,3,4,5-tetramethylphenyl) propan-1-one by a procedure analogous to that of Preparation 2.

³ H NMR (CD ₃ OD) ppm: 3.20 (2H, t), 2.90 (2H, t), 2.85 (3H, s), 2.6 (3H, s), 2.55 ( 3H, s), 2.50 (3H, s).

4,5,6,7-Tetramethyl-l, 2-dione 2-oxime

The title compound was prepared from 4,5,6,7-tetramethylindan-1-one by a procedure analogous to that of Preparation

Third

1 H NMR (d 6 -DMSO) ppm: 12.4 (1H, s), 3.65 (2H, s), 2.7 (3H, s),

2.4 (3H, s); 2.3 (6H, s).

2-Amino-4,5,6,7-tetramethylindan-1-one hydrochloride

The title compound was prepared from 4, 5, 6,7-cetrametylindán-1,2-dione-2-oxime in a similar manner to that of Preparation ^{4; H} NMR (d6-DMSO) ppm: 9.0 (3H, bd s), 4.5 (1H, bdt), 3.7 (1H, dd), 3.2 (IH, dd), 2.8 (3H, s), 2.6 (3H, s), 2 1.5 (6H, 2s).

N- (4,5,6,7-Tetramethyl-1-oxo-indan-2-yl) benzamide

Benzoyl chloride (1.635 g) was added dropwise at 0 ° C to 4,5,6,7-tetramethylindan-1,2-dione-2-oxime (2.53 g) and triethylamine (2.25 g) in anhydrous dichloromethane (60 mL). The reaction mixture was then stirred at room temperature for 1.5 hours, and then the solid product was filtered off, stirred with water (150 ml), filtered again and dried. The organic filtrates were washed with 1 M hydrochloric acid, 10% sodium chloride solution and then dried over magnesium sulfate. After filtration, the solvent was evaporated in vacuo and the product was triturated with diethyl ether, filtered and dried.

NMR (CDCl 3) ppm: 7.8 (2H, d), 7.45 (1H, m), 7.4 (2H, m ·, 6.3 (IH, bd d), 4.6 (1H, m) ), 3.8 (1H, dd), 2.8 (IH, dd), 2.55 (3H,

s), 2.25 (3H, s), 2.15 (6H, 2s).

N- (1-Hydroxy-4,5,6,7-tetramethylindan-2-yl) benzamide

Sodium borohydride (213 mg) was added to N- (4,5,6,7-tetramethyl-1-oxoindan-2-yl) benzamide (495 mg) in chloroform (20 mL) and methanol (20 mL). The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of water (50 mL) and chloroform (20 mL). The aqueous phase was washed with chloroform (2x) and the organic phases were combined, dried over magnesium sulfate, filtered and the solvent was removed in vacuo.

^X 1 HNMR (CDCl ₃₎ ppm: 7.65 (2H, d); 7.4 (IH, m), 7.35 (2H, m); 6.3 (IH, bd d), 5.15 ( 1H, d), 4.5 (IH, m), 3.7 (IH, bd s), 3.5 (IH, dd), 2.65 (IH, dd), 2.25 (3H, s) , 2.15 (9H, 3s).

N- (4,5,6,7-Tetramethylindan-2-yl) benzamide

The title compound was prepared from N- (1-hydroxy-4,5,6,7-tetramethylindan-2-yl) benzamide by a procedure analogous to that described in Preparation 4.

^r H NMR (CDCl3) ppm: 7.65 (2H, d); 7.4 (IH, m), 7.30 (2H, m), 6.25 (IH, bd d), 4.85 (H m), 3.35 (1H, dd), 2.80 (1H, dd), 2.10 (12H, 2s).

Benzyl- (4,5,6,7-Tetramethyl-2-yl) -amine

M Lithium aluminum hydride (2.4 mL) in tetrahydrofuran was added dropwise to a solution of N- (4,5,6,7-tetramethylindan-2-yl) benzamide (352 mL) in anhydrous tetrahydrofuran (10 mL) under nitrogen atmosphere at room temperature. . The reaction mixture was then stirred at 50 ° C for 20 hours. After 4 hours, an additional 1 M solution of lithium aluminum hydride in tetrahydrofuran (1.2 mL, 1.20 mmol) was added. After cooling, the reaction mixture was quenched with ice water. The aqueous phase is extracted with diethyl ether (3x) and the combined organic phases are dried over magnesium sulfate, filtered and the solvent is removed in vacuo.

¹ H NMR (CDCl 3) ppm: 7.25 (4H, m), 7.15 (1H, m), 3.80 (2H, s),

3.55 (1H, m), 3.10 (2H, dd), 2.70 (2H, dd), 2.10 (12H, 2s).

Intermediate 22: Benzyl- (2,3,5,6,7,8-hexahydro-2 H -cyclopenta [i] naphthalen-2-yl) amine

Following the procedure of A.F. Abel-Magid et al., J. Org. Chem., 1966, 61, 3849-3862 was added to a stirred suspension of 2,3,5,6,7,8-hexahydro-222-cyclopenta [b] naphthalen-2-ylamine in 1,2-dichloroethane (30 mL). triethylamine (0.87 mL, 6.17 mmol) at room temperature under a nitrogen atmosphere. Benzaldehyde (0.52 mL, 5.14 mmol) was then added, followed by triacetoxyborohydride (1.64 g, 7.70 mmol) and acetic acid (0.44 mL, 7.70 mmol). The reaction mixture was then stirred at room temperature for 18 hours. After dilution with dichloromethane, the mixture was washed with aqueous sodium hydroxide solution (50 mL, 1 M) and then brine. Evaporation of the solvent and chromatography (silica gel, ethyl acetate / hexane 2: 1) gave the product as an oil.

NMR (CDCl ₃ ) ppm: 1.70 (4H, m), 2.65 (4H, m), 2.68 (2H, dd), 3.05 (2H, dd), 3.58 (1H, m) 1.78 (2H, s), 6.83 (2H, s), 7.25 (5H, m).

Intermediate 23: 2-Methylindan-2-ylamine

2-amino-2-methyl-indan-lon

Following the procedure of Farnum et al., Synthesis, 1972, 191-192, potassium hexacyanoferrate (202 g, 615 mmol) and 2-methylindan-1-one were added to water heated to 80 ° C and degassed by repeated evacuation and flushing with nitrogen (3x). (20 g, 137 mmol). The mixture was stirred rapidly under nitrogen at 80 ° C and an aqueous solution of concentrated ammonia (105 mL) was added over 30 minutes. Stirring was then continued at 80 ° C for 20 hours. After cooling, the mixture was basified by addition of sodium hydroxide (2 g) and extracted with ethyl acetate (2 x 200 mL). The organic extract was concentrated to 200 mL and the product was extracted with aqueous hydrochloric acid (200 mL, 1 M). The acidic aqueous phase was separated, basified with sodium hydroxide and extracted with ethyl acetate (2 x 100 mL). The organic phase was separated, dried over sodium sulfate, and the solvent was evaporated to give an orange-colored oil.

NMR (CDCl ₃ ) ppm: 1.38 (3H, s), 1.8 (2H, br s), 3.07 (1H, d),

3.25 (1H, d), 3.45 (2H, m), 7.65 (1H, t), 7.80 (1H, d).

2.2.2-Trifluoro-N- (2-methyl-1-oxoindan-2-yl) acetamide

2-Amino-2-methylindan-1-one (16.4 g) in tetrahydrofuran (100 mL) was cooled to 0 ° C under a nitrogen atmosphere. Triethylamine (21 mL) was added followed by slow addition of trifluoroacetic anhydride (18.5 mL). The reaction mixture was stirred at room temperature overnight and then the solvent was removed. The residue was dissolved in dichloromethane and washed with aqueous hydrochloric acid solution and then aqueous sodium hydroxide solution. The organic extract was dried over magnesium sulfate and the solvent was evaporated. The product was purified by chromatography (silica gel, ethyl acetate) to give a cream colored solid.

1 H NMR (CDCl 3) ppm: 1.52 (3H, s), 3.44 (1H, d), 3.55 (IH, No),

7.05 (1H, br s), 7.43 (2H, m), 7.70 (1H, t), 7.87 (1H, d).

2.2.2-Trifluoro-(- (2-methylindanyl) acetamide

2,2,2-Trifluoro-N- (2-methyl-1-oxoindanyl) acetamide (3.41 g) in acetic acid (25 mL) and sulfuric acid (0.5 mL) was stirred under a hydrogen atmosphere in the presence of 10 % palladium on carbon for 18 hours at room temperature. The mixture was filtered through celite and the filtrate was concentrated in vacuo. After dilution with water, the mixture is extracted with diethyl ether. The organic phase is separated, washed several times with aqueous sodium bicarbonate solution and dried over sodium sulfate. Evaporation of the solvent gave an oil which solidified.

1 H-NMR (CDCl 3) ppm: 1.55 (3H, s), 3.05 (2H, d), 3.28 (2H, d),

6.28 (1H, br s), 7.12 (4H, s).

2-methyl-indan-2-ylamide

A stirred solution of 2,2,2-trifluoro-N- (2-methylindan-2-yl) acetamide (6.70 g) and sodium hydroxide (4.0 g) in methanol (100 mL) and water (1.0 mL) ) was heated at 70 ° C for 2 hours. The solvent was evaporated and the residue was partitioned between aqueous hydrochloric acid (100 mL, 2 M) and ethyl acetate (100 mL). The aqueous extract was separated, basified with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phase is separated, dried over magnesium sulphate and evaporated to give an orange-colored oil which solidifies.

³ H NMR (CDCl ₃ ) ppm: 1.19 (3H, s), 1.50 (2H, br s), 2.65 (2H, d),

2.79 (2H, d); 6.97 (4H, m).

Intermediate 24: 2-Methyl (2, 3, 5, 6, 7,8-hexahydro-2 H -cyclopene-a [b] naphthalen-2-yl) amine

1- (5,6,7,8-Tetrahydronaphthalen-2-yl) propan-1-one

Propionyl chloride (17.5 mL) and 1,2,3,4-tetrahydronaphthalene (27.5 mL) were slowly added over 1 hour to a stirred solution of aluminum chloride (61.3 g) in nitromethane (200 mL) at 0 C. The reaction mixture is stirred for 18 hours at room temperature and then carefully added to a mixture of ice and concentrated hydrochloric acid. The product was extracted with ethyl acetate, washed with brine and dried over sodium sulfate.

^{Χ Η} NMR (CDCl3) ppm: 1.15 (3H, t), 1.72 (4H, m), 2.72 (4H, m),

2.88 (2H, q), 7.04 (1H, d), 7.60 (1H, m).

2-Methyl-2,3,5,6,7,8-hexahydro-2H-cyclopenta [b] naphthalen-1-one.

Following the procedure of Battacharya et al., Synth. Commun., 1956, 26, 1775-1784 with a mixture of 1 '(5,6,7,8-tetrahydronaphthalen-2-yl) -cappan-1'-one (37.6 g), hexamethylenetetraamine (44.9 g) and acid anhydride Acetic acid (38.8 g) was heated at 80 ° C for 23 hours. The reaction mixture was allowed to cool and then slowly added to a stirred mixture of ethyl acetate (200 mL) and aqueous sodium hydroxide solution (200 mL, 2 M). The organic phase was separated, washed with aqueous hydrochloric acid solution, brine and dried over sodium sulfate. The solvent was evaporated to give a brown oil. This was carefully added to concentrated sulfuric acid (120 mL) and the resulting mixture was then heated at 55 ° C for 5 hours followed by 18 hours at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. After drying over sodium sulfate, the solvent was evaporated to give an oily product which was purified by chromatography (silica gel, ethyl acetate / hexane). A mixture of geometric isomers consisting of 2-methyl-1,2,6,7,8,9-hexahydro-1H-cyclopenta [a] naphthalen-3-one and the title compound is obtained.

^X 1 HNMR (CDCl ₃₎ ppm: 1.40 (3H, m), 1.90 (4H, m), 2.50-3.00 (6H, m), 3.35 (H, m), 7 15 (1H, m), 7.55 (1H, m).

2,2,2-Trifluoro-N- (2-methyl-1-oxo-2,3,5,6,7,8-hexahydro-1H-cyclopenta [b] naphthalen-2-yl) acetamide

The compound is prepared from a mixture of isomers containing 2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta [b] naphthalen-1-one, following the procedure used to prepare 2,2,2-trifluoro-N. - (2-methyl-l-oxo-indan-2-yl) acetamide. The isomeric mixture of products was recrystallized from ethyl acetate / hexane to give a 4: 1 mixture of isomers to give the title compound.

H HNMR (CDCI3) ppm (major component): 1.55 (3H, s), 1.85 (4H, m),

2.87 (4H, m), 6.88 (1H, br s), 7.18 (1H, s), 7.57 (1H, s).

TOF MS ES 'm / e = 310 (M-H')

2-Mety1-2,3,5,6,7,8-hexahydro-cyclopenta [b] naphthalen-2-ylamine

4: 1 geometric isomer mixture consisting predominantly of 2,2,2-trifluoro-N- (2-methyl-oxo-2,3,5,6,7,8-hexahydro-2H-cyclopenta [b] naphthalene-2- yl) acetamide is hydrogenated on palladium on carbon in acetic acid / sulfuric acid, and the product is then saponified with sodium hydroxide as described for the preparation of 2-methylindan-2-ylamine. The resulting mixture of products was recrystallized repeatedly from hexane to give the title compound as one isomer.

^{Χ Η} NMR (CDC1 ₃₎ ppm: 1.40 (3H, s), 1.60 _(NH2, br s), 1.75 (4H, m),

3.75 (4H, m), 2.78 (2H, d), 2.94 (2H, d), 6.93 (2H, s).

Intermediate 25: 2-Ethylindan-2-ylamine

2-Etylindan-l-one

The title compound was prepared analogously to the procedure described for the preparation of 2-methyl-2,3,5,6,7,8-hexahydrocyclopenta [b] naphthalen-1-one.

^X H NMR (CDCl3) ppm: 0.97 (3H, t), 1.50 (H, m), 1.90 (H, m), 2.55 (H, m), 2.75 (H, dd), 3.25 (1 H, q), 7.29 (1 H, t), 7.39 (1 H, d), 7.50 (1 H, t), 7.69 (1 H, d).

2-Etylindan-2-ylamine

The title compound was prepared from 2-ethylindan-1-one according to the procedure used in the preparation of Intermediate 23.

NMR (CDCl 3) ppm: 1.05 (3H, t), 1.50 (NH ₂ , br s), 2.70 (2.4, q),

2.75 (2H, d), 3.01 (2H, d), 7.20 (4H, m).

Intermediate 26: 2,5,6-Trimethylindan-2-ylamine

The title compound was prepared according to the procedure for the preparation of 2-methyl-2,3,5,6,7,8-hexahydro-2H-cyclopenta [b] naphthalen-2-ylamine.

^X 1 HNMR (CDCl ₃₎ ppm: 1.29 (3H, s), 2.16 (6H, s), 2.69 (2H, d),

2.84 (2H, g), 2.89 (2H, s).

Intermediate 27: Acetic acid (R) -1- (3-Amino-4-benzyloxyphenyl) -2- [benzyl (2-methylindan-2-yl) amino] ethyl ester (R) -2- [Benzyl- (2 methylindan-2-yl) amino] -4-benzyloxy-3-nitro-phenyl) -ethanol

The title compound was prepared from (R) -2- (4-benzyloxy-3-nitrophenyl) oxirane (2.52 g) and benzyl (2-methylindan-2-yl) amine (2.20 g) according to the procedure described in used in the preparation of β-8-benzyloxy-5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -1H-quinolin-2-one in Example 19. According to TLC, the reaction was complete in 24 hours . The product was purified by flash column chromatography (silica gel, n-hexane / ethyl acetate 4: 1). TLC (silica gel, n-hexane / ethyl acetate 4: 1 Rf = 0.30).

1 H NMR (CDCl 3, 400 MHz)? MHz ) δ: 1.20 (3H, with) , 2.65 (IH, m), 2 75 (IH, m), 2.90 (2H, m) , 3.25 ( 2H, m) 1.60 (IH, d), 3 70 (IH, broad), 3.80 ( IH, dd), 4.10 (IH, d), 5.20 (2H, with) , 7 00

(1H, d), 7.20 (4H, m), 7.35 (11H, m), 7.60 (1H, d).

Acetic acid (R) -2- [benzyl- (2-methyl-indan-2-yl) amino] -1- (4-benzyloxy-3-nitro-phenyl) -ethyl ester (R) -2- [Benzyl] - (2-methylindan-2-yl) amino] -4-benzyloxy-3-nitrophenyl) ethanol (2.75 g) was dissolved in pyridine (15 mL), acetic anhydride (1.66 g) was added and the reaction the mixture is stirred at room temperature. TLC indicated that the reaction was complete after 18 hours. Water (10 mL) was added to quench the reaction. Ethyl acetate (250 mL) was added and the solution was washed with potassium hydrogen sulfate, saturated sodium bicarbonate solution (100 mL), water (100 mL) and brine (100 mL). The organic phase is dried over magnesium sulphate, filtered and the solvent is evaporated off under vacuum. The product is not further purified. TLC (silica gel, n-hexane / ethyl acetate 4: 1 Rf = 0.40).

NMR (CDCl3, 400 ΜΗζ) δ: 1.20 (3H, s), 1.90 (3H, s), 2.80 (3H, m) , 3.00 (1H, d), 3.10 (IH, m), 3.20 (IH, d), 3.75 (IH, d) 3, 90 ( IH, d) 5.20 (2H, s) 5.25 (1H, m), 6.95 (IH, d), 7.10 (3H, m) , 7.30 (11H, m) 7.55 (1 H, d).

Acetic acid (R) -i- (3-Amino-4-benzyloxyphenyl) -2- [benzyl- (2-methylindan-2-yl) amino] ethyl ester

The title compound was prepared from acetic acid (R) -2- [benzyl- (2-methylindan-2-yl) amino] -1- (4-benzyloxy-3-nitrophenyl) ethyl ester by the procedure described in Preparation (R). The 1- (3-amino-4-benzyloxyphenyl) -2- [benzyl- (5,6-diethylindan-2-yl) amino] ethanol in Example 19. TLC indicated that the reaction was complete after 6 hours. The catalyst was filtered off and the solvent was evaporated

under vacuum. The product is further unclean. TLC (Silica gel, n-hexane / ethyl acetate 2: 1 Rf = 0.60). ¹ H NMR (CDCl 3, 400 ΜΗζ) δ: ; 1,20 1 (3H, s) 1.80 (3H, s) 2.70 (3H, m) 3.05 (2H, m) 3.15 (IH, d) 3.65 (2H, broad) 3.75 (1H, d), 3.90 (IH, d), 4.95 (2H, s), 5.20 (1H, m), 6.40 (2H, m) 6.65 (1H, d) 7.20 (14H, m).

Intermediate 28: Benzyl- (2,5,6-trimethylindan-2-yl) amine

N- (2,3,6-Trimethylindan-2-yl) benzamide

Intermediate 26 was treated with benzoyl chloride in a mixture of dichloromethane and triethylamine for 1 hour. The reaction mixture was washed with 1 N hydrochloric acid, then with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residue was triturated in diethyl ether / hexane to give white crystals.

^ς Η NMR (CDCl ₃ ) ppm: 1.60 (3H, s), 2.18 (6H, s), 3.02 (2K, d),

3.30 (2H, d), 6.17 (NH, br s), 6.90 (2H, s), 7.34 (2H, m), 7.40 (1H, m), 7.63 (2H, m) IH, d).

Benzyl- (2,5,6-trimethyl-2-yl) -amine

To a solution of N- (2,5,6-trimethylindan-2-yl) benzamide in tetrahydrofuran was added lithium aluminum hydride under a nitrogen atmosphere, and the reaction mixture was heated under reflux for 48 hours. After cooling, the reaction was quenched at 0 ° C by the addition of ice and water and extracted with diethyl ether, dried over sodium sulfate and the solvent was evaporated in vacuo. Purification by chromatography (silica gel, ethyl acetate / hexane 1: 4 ') afforded a colorless oil.

^X 1 HNMR (CDCl ₃₎ ppm: 1.58 (3H, s), 1.79 (NH, br s), 2.40 (6H, s),

3.00 (2H, d), 3.20 (2H, d), 3.99 (2H, s), 7.15 (2H, s),

7.37-7.53 (5 H, m).

Intermediate 29: Acetic acid (R) -1- (3-Amino-4-benzyloxyphenyl) -2- [benzyl (2,5,6-trimethylindan-2-yl) amino] ethyl ester (R) -1- (4-) benzyloxy-3-nitrophenyl) -2- [benzyl- (2,5,6-trimethyl-indan-2-yl) amino] ethanol

A mixture of 2- (4-methyl-3-nitrophenyl) oxirane and benzyl- (2,5,6-trimethylindan-2-yl) amine was heated at 110 ° C for 48 hours. The material was used without further purification.

ES ⁺ MS m / e = 538 (MH &lt; ^{+ &gt;} ).

Acetic acid (RJ-1- (4-Benzyloxy-3-nitrophenyl) -2- [benzyl- (2,5,6-trimethylindan-2-yl) amino] ethyl ester

To a solution of (R) -1- (4-benzyloxy-3-nitrophenyl) -2- [benzyl (2,5,6-trimethylindan-2-yl) amino] ethanol in pyridine was added acetic anhydride and the reaction mixture was stirred 18 hours. The reaction mixture is quenched by the addition of water and, after the addition of ethyl acetate, the organic phase is washed twice with aqueous potassium hydrogen sulphate solution, twice with aqueous sodium hydrogen carbonate solution and once with sodium chloride solution. The product is purified by chromatography (silica gel, ethyl acetate / hexane 1: 4). ES ⁺ MS m / e = 579 (MH &lt; ^{+ &gt;} ).

Acetic acid (R) -1- (3-amino-4-benzyloxyphenyl) -2- [benzyl- (2,5,6-trimethylindan-2-yl) amino] ethyl ester (R) -1- (4-Benzyloxy) Acetic acid -3-nitrophenyl) -2- [benzyl- (2,5,6-trimethylindan-2-yl) amino] ethyl ester was stirred in a mixture of tetrahydrofuran and toluene under a hydrogen atmosphere in the presence of platinum oxide for 15 hours. The reaction mixture was then filtered through celite and the filtrate was concentrated in vacuo. ES ⁺ MS m / e = 549 (MH &lt; ^{+ &gt;} ).

Intermediate 30: 5,6-Diethyl-2-methylindan-2-ylamine

N- (5-Acetyl-2-methyl-indan-2-yl) -benzamide

Aluminum chloride (3.7 g) was dissolved in nitromethane (12 mL) and N - (2-methylindan-2-yl) benzamide (3.0 g) was added under nitrogen at 0 ° C. Acetyl chloride (0.85 mL) was then added over 30 minutes. After 4 hours at room temperature, the reaction was quenched by the addition of ice and concentrated hydrochloric acid and extracted with dichloromethane. The organic phase is washed with dilute hydrochloric acid and brine. Evaporation of the solvent gave the desired product. ES * MS m / e = 294 (MH &lt; ^{+ &gt;} ).

N- (5-ethyl-2-methyl-indan-2-yl) -benzamide

A solution of N- (5-acetyl-2-methylindan-2-yl) benzamide (3.4 g) in ethanol (200 ml) and concentrated hydrochloric acid (2 ml) was stirred for 48 hours at room temperature under a hydrogen atmosphere in the presence of 10 ml. % palladium on charcoal. The mixture was then filtered through celite, the filtrate was concentrated in vacuo to give the title compound.

NMR (CDCl ₃ ) ppm: 1.20 (3H, t), 1.60 (3H, s), 2.55 (2H, g), 3.05 (2H, d), 3.35 (2H, d) 6.35 (NH, br s), 6.93-7.10 (3H, m), 7.39 (2H, d), 7.65 (2H, s).

N- (5-acetyl-6-ethyl-2-methyl-indan-2-yl) -benzamide

The title compound was prepared from N- (5-ethyl-2-methylindan-2-yl) benzamide (2.6 g) according to the procedure used to prepare N- (5-acetyl-2-methylindan-2-yl) benzamide. The product was purified by chromatography (silica gel, hexane / ethyl acetate, 4: 1) to give the title compound. ES ^T MS m / e = 322 (MH &lt; ^{+ &gt;} ).

N- (5,6-diethyl-2-methyl-indan-2-yl) -benzamide

The title compound was prepared from N- (5-acetyl-6-ethyl-2-methylindan-2-yl) benzamide (1.1 g) according to the procedure used to prepare N- (5-ethyl-2-methylindan-2- yl) benzamide. ES ⁺ MS m / e = 308 (MH &lt; ^{+ &gt;} ).

Benzyl- (5,6-diethyl-2-methylindan-2-yl) amine

The title compound was prepared from N- (5,6-diethyl-2-methylindan-2-yl) benzamide in an analogous manner used to prepare benzyl- (5,6-diethylindan-2-yl) amine in Intermediate 18. ES ⁺ MS m / e = 294 (MH +).

5,6-Diethyl-2-methyl-indan-2-ylamine

A solution of benzyl- (5,6-diethyl-2-methylindan-2-yl) amine (0.48 g) in methanol (10 mL) was stirred at room temperature under a hydrogen atmosphere in the presence of 10% palladium on carbon for 18 hours. The mixture was filtered through celite, and the filtrate was concentrated in vacuo to give the title compound. ES ^T MS m / e = 204 (MH &lt; ^{+ &gt;} ).

Example 1 (R) -8-Benzyloxy-5- [2- (4,7-dimethoxyindan-2-ylamino) -1-hydroxyethyl] -2H-quinolin-2-one (R) -8-Benzyloxy-5-oxiranylcarbostyril (100 mg, 0.34 mmol) prepared according to the procedure of (Beeley, Lee; James, Dean; David

Kenneth, PCT Appl: WO 9525104) and 4,7-dimethoxyindan-2-ylamine (66 mg, 0.34 mmol) prepared according to the procedure described by Sindelar, RD, Mott, J., Barfknecht, CF, Arneric, SP, Flynn, JR. Long, JP, Bhatnagar, RK, J. Med. Chem. (1982, 25 (7), 858-864), was dissolved in toluene (1 mL). The reaction mixture was heated to 110 ° C and the solvent was allowed to evaporate. The residue is then stirred at 110 ° C for 4 hours. TLC indicated that the reaction was complete. The product was purified by flash chromatography (silica gel, dichloromethane / methanol 20: 1).

TLC (silica gel, dichloromethane / methanol 25: 1 Rf = 0.60). ES - MS m / e = 487 (MH ⁺ ).

(R) -8-Hydroxy-5- [2- (4,7-dimethoxyindan-2-ylamino) -1-hydroxyethyl] -1H-quinolin-2-one hydrochloride (R) -8-Benzyloxy-5- [2- (4,7-Dimethoxyindan-2-ylamino) -1-hydroxyethyl] -2H-quinolin-2-one (37 mg, 0.08 mmol) was dissolved in methanol (10 mL). The protecting group is removed by hydrogenation under an atmosphere of hydrogen in the presence of a catalytic amount of 10% palladium on carbon. TLC indicated complete reaction after 4 hours. The catalyst was filtered off, 1 M hydrogen chloride in diethyl ether (1.1 equivalents) was added and the solvent was evaporated in vacuo.

TLC (silica gel, dichloromethane / methanol 10: 1 Rf = 0.15). ES - MS m / e = 397 (MH ⁺ ).

Other compounds of formula I are prepared from (R) -8-benzyloxy-5-oxiranylcarbostyril (R) -2- (4-benzylcxy-3-nitrophenyl) oxirane (Intermediate 15 in Example 11) and the corresponding compounds of formula XVII, following the procedure of according to Example 1. The compounds in which R * is a hydroxyl group, R and R 'are n Q hydrogen atoms, Ar is a group of formula III, wherein R,

R ³⁰ and R ³¹ are hydrogen atoms (except Example 11 where Ar is a group of formula XV wherein R ¹³ is hydrogen and n is 1 (except Example 9 where n is 2) are shown in the following table.

Example R ⁴ R ⁵ R ⁶ R ⁷ ES + MS m / e (MH &lt; ^{+ &gt;} ) 2 H CH3CH2 ch ₃ ch ₂ H 393 3 H ch ₃ ch ₃ H 365 4 CH ₃ CH ₂ H H CH ₃ CH ₂ 393 5 H - (CH ₂ ) ₄ - H 391 6 H -0 (CH ₂ ) ₂ o- H 395 7 H CH ₃ (CH ₂ ) ₃ CH ₃ (CH ₂ ) ₃ H 449 8 H CH ₃ (CH ₂ ) 2 CH ₃ (CH ₂ ) 2 H 421 9 H H H H 365 10 H CH ₃ OCH ₂ CH ₃ OCH ₂ H 11 H ch ₃ ch ₂ ch ₃ ch ₂ H 341

Example 10: ¹ H NMR (d ₄ -MeOH; l ppm: 2,78 ( 2H, m) 2.90 (2H, m) 3.15 (2 H, m), 3.28 (6H, s) 3.70 (IH, m) 4.55 (1H, br s), 5.15 (IH, m), 6.58 (IH, d) 6.90 (1H, d), 7.11 (2H, s) 7.15 (IH, s)

8.25 (1H, s).

Example 12

8-Hydroxy-5- [l-hydroxy-2- (indan-2-ylamino) -ethyl] -lH-quinolin-2-one

Intermediate 10 (18 mg, 0.054 mmol) was dissolved in methanol (2 mL) and cooled with ice. Sodium borohydride (6 mg, 0.12 mmol) was added over 2 hours. Concentrated hydrochloric acid is then added until the reaction mixture has a pH = 1 and then filtered. The filtrate was washed with methanol. The combined liquid phases are evaporated, redissolved in methanol. After removal of the methanol in vacuo, the residue was dissolved in water and adjusted to pH 12 by addition of 1 N potassium hydroxide. The solvent was evaporated in vacuo and the residue was evaporated twice with toluene. The residue was purified by flash chromatography (silica gel, dichloromethane / methanol 8: 2).

Example 13

5- [2- (5,6-dimethoxyindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-lH-quinolin-2-one

This compound was prepared from Intermediate 11 by a procedure analogous to that described in Example 12. ES ⁺ MS m / e = 397 (MH ⁺ ).

Example 14

5- [2- (5,6-Diethylindan-2-ylamino) -1-hydroxyethyl] -8 hydroxy-3-methyl-1H-quinolin-2-one

This compound was prepared from Intermediate 13 (21 mg) by a hydrogenation procedure to remove the benzyl group used in Example 1.

NMR (d ₄ -MeOH) ppm: 1.11 (6H, t), 2.11 (3H, s), 2.58 (4H, q),

3.01-3.37 (6H, m), 4.10-4.16 (1H, m), 5.31-5.38 (1H, m), 6.91 (1H, d), 7, Δ (2H, s), 7.21 (1H, d), 8.13 (1H, s).

Example 15

5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl] -8-methoxymethoxy-6-methyl-2H-quinolin-2-one

This compound was prepared from Intermediate 14 (20 mg) a

5,6-diethylindar-2-ylamine (72 mg) according to the procedure used in the preparation of Intermediate 13.

NMR (CDCl ₃ ) ppm: 1.14 (6H, t), 2.30 (3H, s), 2.51 (4H, q), 2.64-3.16 (6H, m), 3.41 (3H, s), 3.60-3.68 (1H, m), 5.18-5.25 (3Η, m), 6.50 (IH, d), 7.89-7, 94 (3H, s) , m), 8.68 (2H, d), 9.15 (1H, br s).

5- [2- (5,6-Diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-6-methyl-1H-quinolin-2-one To a solution of 5- [2- (5,6-diethylindan) -2-ylamino) -1-hydroxyethyl] -8-methoxymethoxy-6-methyl-2H-quinolin-2-one (12 mg) in isopropanol (1 mL) at room temperature is added 3 N hydrochloric acid (1 mL) and the reaction mixture was heated at 40 ° C for 18 hours. The solvent was evaporated in vacuo and the product was purified by preparative high pressure liquid chromatography (HPLC) on a C8 column, eluting with a water / acetonitrile / trifluoroacetic acid gradient.

¹³ C NMR (d ₄ -CH ₃ OH) ppm: 15.97; 20.09; 26, 34; 36.87; 51.75; 59.72; 67.33; 118.41; 119.12; 121.21; 125.45; 126.11; 128.60; 133.35; 137.52; 137.55; 142.32; 142.50; 145.69; 163.24.

Example 16

8-Hydroxy-5- [2- (5,6-diethyl-indan-2-ylamino) -ľhydroxy-ethyl] -3,4-dihydro-2H-quinolin-2-one

Hydrogenation of 8-hydroxy-5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -2H-quinolin-2-one (Example 2) in a solution of methanol and ethanol to 10% palladium on carbon in under a hydrogen atmosphere at 30 ° C for 48 hours to give the title compound. After filtration and evaporation, further purification is performed by preparative HPLC (Phenomenex Luna 10 µm 150 mm x 50 mm column, eluent: gradient from 10% to 95% acetonitrile in water containing 0.1% trifluoroacetic acid, detection (JV at 254 nm) ).

¹³ C NMR (d 6 -DMSO) ppm: 15.77; 21.42; 25.01; 30.37; 37.73; 37.83; 53.88; 58.68; 67.37; 113.28; 120.21; 122.08; 124.31; 124.34; 131.01; 138.46; 138.52; 139,58; 143,12; 169.44.

Example 17 (a) (R) -1- (4-Benzyloxy-3-formylaminophenyl) -2- [benzyl- (2,5,6-trimethylindan-2-yl) amino] ethyl acetate

To intermediate 29 in toluene / tetrahydrofuran was added a mixture of formic acid and acetic anhydride with stirring, and the reaction mixture was stirred at room temperature for 5 hours. Ethyl acetate is then added and the organic phase is washed with sodium bicarbonate solution. Chromatographic purification (silica gel ethyl acetate / hexane 1: 2) and trituration with diethyl ether gave almost white crystals. ES ⁺ MS m / e = 577 (MH &lt; + &gt;).

(b) N- (Benzyloxy-5 - {(R) -2- [benzyl- (2,5,6-trimethylindan-2-yl; amino] -1-hydroxyethyl} phenyl) formamide

The product of Example 17 (a) is suspended in ethanol and a catalytic amount of sodium methoxide in methanol is added. After two hours at 70 ° C the solvent was evaporated and the residue was purified by chromatography (silica gel ethyl acetate / hexane 2: 3) to give white crystals. ES ⁺ MS m / e = 535 (MH &lt; ^{+ &gt;} ).

(c) N- {2-Hydroxy-5 - [(R) -1-hydroxy-2- (2,5,6-trimethylindan-2-ylamino) ethyl] phenyl} formamide

The title compound was prepared from the product prepared in Example 17 (b) by the procedure described in Example 34 (c). ES ⁺ MS m / e = 355 (MH &lt; ^{+ &gt;} ). '

Example 18 (a) 8-Benzylamino-5 - [(R) -2- (5,6-diethyl-2-methylindan-2-ylamino) -1-hydroxyethyl] -1H-quinolin-2-one

A mixture of 5,6-diethyl-2-methylindan-2-ylamine (0.28 g) and 8-cenzyloxy-5-oxiranyl-1H-quinolin-2-one (0.42 g) in n-butanol is placed in Prolabo. microwave for 75 minutes at 100 ° C.

The product is then purified by chromatography (silica gel, dichloromethane / ethanol 5: 1) to give the desired product. ES ⁺ MS m / e = 497 (MH &lt; ^{+ &gt;} ).

5- [f] -2- (5,6-Diethyl-2-methylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-2H-quinolin-2-one

A solution of the product of Example 18 (a) (0.20 g) in methanol (20 mL) was stirred for 2 hours at room temperature under a hydrogen atmosphere in the presence of 10% palladium on carbon. The mixture was then filtered through celite and the filtrate was concentrated in vacuo. Grinding in diethyl ether gives the desired product. ES ⁺ MS m / e = 407 (MH &lt; ^{+ &gt;} ).

Example 19 (a) (S) -8-Benzyloxy-5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -27H-quinolin-2-one

The title compound was prepared from Intermediate 15 (152 mg) and Intermediate 1 (100 mg) using the procedure of Example 1 (a). TLC (silica gel, dichloromethane / methanol 10: 1 Rf = 0.25).

(b) [5] -5- (2- (4,7-Diethylindan-2-ylamino) -1-hydroxyethyl) -1H-quinolin-2-one hydrochloride

The title compound was prepared from the product of Example 19 (a) according to the procedure described in Example 1 (b). TLC (silica gel, dichloromethane / methanol 10: 1 Rf = 0.05).

Example 20 (a) 8-Benzyloxy-5 - [(R) -1-hydroxy-2- (6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino) ethyl] -2H-quinolin-2- one

The title compound was prepared from (R) -8-benzyloxy-5-oxiranylcarbostyril (203 mg) and Intermediate 17 (110 mg) according to the procedure of Example 1 (a). TLC (silica gel, dichloromethane / methanol 10: 1 Rf = 0.30).

(b) 5 - [(R) -1-Hydroxy-2- (6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino) ethyl] -1H-quinolin-2-one hydrochloride

The title compound was prepared from the product of Example 20 (a) by the procedure of Example 1 (b). TLC (silica gel, dichloromethane / methanol 10: 1 Rf = 0.05).

Example 21 (a) (R) -8-Benzyloxy-5 - ((S) -2- [benzyl- (5,6-diethylindan-2-yl) amino] -1-hydroxyethyl} -1H-quinoline- 2-one

A solution of (R) -8-Benzyloxy-5-oxiranylcarbostyril (5.00 g) and 2-amino-5,6-diethylindane (3.87 g) in n-butanol was heated at 110 ° C for 4 hours. After cooling to room temperature, the organic phase is washed with water (3 x 25 ml), applied to a silica gel chromatography column and eluted first with toluene and then with toluene: ethanol: ethyl acetate: horses.

ammonia (45: 10: 45: 2) to give the title compound.

(b) (R) -5- [2- (5,6-Diethylindan-2-ylamino) -1-hydroxyethyl] -1H-quinolin-2-one maleate (R) -8-Benzyloxy-5- [2- (5,6-Diethylindan-2-ylamino) -1-hydroxyethyl] -1H-quinolin-2-one (360 mg) was dissolved in methanol (10 mL) and the protecting group was removed by adding a catalytic amount of 10% palladium on carbon and hydrogenation in an atmosphere of hydrogen. TLC indicated that the reaction was complete in 4 hours. The catalyst was filtered off and the solvent was removed in vacuo. The product was dissolved in isopropanol and maleic acid in isopropanol was added. The title compound is obtained after crystallization from ethanol. TLC (silica gel, dichloromethane / methanol 10: 1 Rf = 0.05). ES ⁺ MS m / e = 393 (MH &lt; ^{+ &gt;} ).

Example 22 (a) N- (5 - {(R) -2- [benzyl- (5,6-diethylindan-2-yl) amino] -1-hydroxyethyl} -2-benzyloxyphenyl) formamide

The title compound was prepared from Intermediate 19 (1.00 g), formic acid (155 mg) and acetic anhydride (226 mg) using the procedure described in Example 21 (a). TLC (silica gel, n-hexane / ethyl acetate 2: 1 Rf = 0.20).

(b) N- {5 - [(R) -2- (5,6-diethylindan-2-yl) amino] -1'-hydroxyethyl] -2-hydroxyphenyl} formamide

The title compound was prepared from the product of Example 22 (a) following the procedure of Example 1 (b). TLC (silica gel, n-hexane / ethyl acetate 2: 1 Rf = 0.05).

Example 23 (a) (R) -2- [Benzyl- (5,6-diethylindan-2-yl) amino] -1- (4-benzyloxy-3-dimethylaminophenyl) ethanol

Intermediate 19 (0.37 g) was dissolved in methanol (50 ml) and formaldehyde, 37% in water (5 ml) dissolved in water (10 ml) was added. A catalytic amount of platinum oxide is then added and the reaction mixture is stirred under a hydrogen atmosphere. TLC indicated that the reaction was complete after 24 hours. The catalyst was filtered off, the solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The organic phase is dried over magnesium sulphate and the solvent is evaporated off under vacuum. The product was purified by flash column chromatography (silica gel, n-hexane / ethyl acetate 4: 1). TLC (silica gel, n-hexane / ethyl acetate 2: 1 Rf = 0.65).

(b) 4- [trans-2- (5,6-Diethylindan-2-ylamino) -1'-hydroxyethyl] -2-dimethylaminophenol hydrochloride

The title compound was prepared from the product of Example 23 (a) by the procedure of Example 1 (b).

⁷ H-NMR (DMSO, 400 MHz)? MHz) δ: 1.10 (6H, t), 2.55 (4H, q); 3.05 (2H, m), 3.10 (6H, s J, 3.20 (4H, m) , 4, 00 ( 1H, m) 4.95 (IH, m), 7.00 (2 H, s), 7.15 (1H, d) 7.35 (IH, d) , 7.80 (IH, WITH) , 9, 20 (IH, broad), 9.75 ( IH, broad), 11 40 (IH, br)

Example 24 (a) (R) -2- [Benzyl- (5,6-diethylindan-2-yl) amino] -1- (4-benzyloxy-3-methylaminophenyl) ethanol

The product of Example 22 (260 mg) was dissolved in dioxane (20 mL). Sodium borohydride was added followed by dropwise addition of acetic anhydride (142 mg). The reaction mixture was then stirred at 90 ° C. According to TLC, the reaction was complete after 4 hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase is dried over magnesium sulphate, filtered and the solvent is evaporated off under vacuum. The product was purified by flash column chromatography (silica gel, n-hexane / ethyl acetate 4: 1). TLC (silica gel, n-hexane / ethyl acetate 2: 1 Rf = 0.65).

(b) 4 - [(RJ-2- (5,6-Diethylindan-2-ylamino) -1-hydroxyethyl] -2-methylaminophenol hydrochloride

The title compound was prepared from the product of Example 24 (a) following the procedure of Example 1 (b).

⁴ H NMR (DMSO, 400 MHz) δ: 1.10 (6H, t), 2.55 (4H, q), 2.85 (3H, m), 3.10 (6H, m), 3.20 (4H, m), 4.00 (1H, m), 4.90 (IH, m), 7.00 (2H, m), 7.15 (IH, m), 7.40 (IH, m) , 9.10 (1H, broad),

9.60 (1H, broad), 10.80 (1H, broad).

Example 25 (a) N- (5 - {[Benzyl- (5,6-diethylindan-2-yl) amino] acetyl} -2-benzyl59 oxyphenyl) methanesulfonamide

Intermediate 20 (240 mg) was dissolved in dichloromethane (10 mL). Triethylamine (56 mg) was added followed by methanesulfonyl chloride (58 mg). The reaction mixture is stirred at room temperature. TLC indicated that the reaction was complete after 24 hours. The solvent was evaporated in vacuo and the product was purified by flash column chromatography (silica gel, n-hexane / ethyl acetate 4: 1). TLC (silica gel, n-hexane / ethyl acetate 2: 1 Rf = 0.40).

(b) N- (5- {2- [Benzyl- (5,6-diethylindan-2-yl) amino] -1-hydroxyethyl} -2-benzyloxyphenyl) methanesulfonamide

The product of Example 25 (a) (120 mg) was dissolved in ethanol (10 mL). Sodium borohydride (9 mg) was added and the reaction mixture was stirred at room temperature. TLC indicated complete reaction after 3 hours. The reaction was quenched by the addition of 2M hydrochloric acid (1 mL), the solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (50 mL). The organic phase is dried over magnesium sulphate, filtered and the solvent is removed in vacuo. The product was not further purified. TLC (silica gel, n-hexane / ethyl acetate 2: 1 Rf = 0.45).

(c) N- {5- [2- (5,6-Diethylindan-2-ylamino) -1'-hydroxyethyl] -2-hydroxyphenyl} methanesulfonamide hydrochloride

The title compound was prepared from the product of Example 25 (b) according to the procedure of Example 1 (b).

⁷ H NMR (CDCl ₃ , 400 MHz) δ: 1.15 (6H, t), 2.55 (4H, q) z 2, 95 (3H, s), 3.10 (6H, m), 4.00 (IH , m), 4.85 (IH, m), 6, 10 (IH, broad), 6, 90 (2H, d), 7.00 (2H, s) 7.10 (IH, dd), 7.25 (1H, d) 8.75 (IH, with) , 3.95 '(IH, wide), 9.25 (IH, are you. years); 10.00 (1H, s).

Example 26 (a) 8-Benzyloxy-5 - ((S) -2- [benzyl (4,5,6,7-tetramethylindan-2-yl) amino] -1'-hydroxyethyl} -2H-quinolin-2-one (R) 1-8-Benzyloxy-5-oxiranylcarbostyril (204 mg) and intermediate 21 (194 mg) were dissolved in n-buzanole under nitrogen.

The reaction mixture was then heated at 110 ° C for 22 hours. After cooling, the solvent was evaporated in vacuo. The product was purified by flash column chromatography (silica gel / ethyl acetate / hexane 50:50). ES ⁺ MS m / e = 573 (MH &lt; ^{+ &gt;} ).

(b) (R) -8-Hydroxy-5 - [(S) -1'-hydroxy-2- (4,5,6,7-tetramethylindan-2-ylamino) ethyl] -1H-quinolin-2-one

The title compound was prepared from the product of Example 26 (a) following the procedure of Example 1 (b).

NMR (CD ₃ OD)? Ppm: 8.55 (IH, d), 7.50 (H, d), 7.25 (H, d),

6.9 (1H, d), 5.60 (1H, m), 4.30 (IH, m), 3.70 (2H, q), 3.60 (2H, dd), 3.30 (2H , dd), 2.40 (12H, s).

Example 27 (a) 8-Benzyloxy-5 - [(R) -1'-hydroxy-2- (2-methylindan-2-ylamino) ethyl] -1H-quinolin-2-one

A mixture of 8-benzyloxy-5- (R) -oxiranyl-1H-quinolin-2-one (505 mg) and 2-methylindan-2-ylamine (276 mg) in n-butanol (1 mL) was heated in a Prolabo microwave oven. Synthewave 402 for 90 minutes at 110 ° C. The residue is absorbed onto silica gel and the product is purified by flash chromatography (silica gel, chloroform / ethanol 4: 1).

’H nn IR (CDC13) ppm: 1.30 (3H, s) 2.65 (IH, with) , 2, 95 (2H, dd) 3, 07 (3H, m) 5, 15 (IH, m), 5.18 (2H, with) , 6, 66 (IH, d), 7.17 (4H, m), 7.26 (IH, d), 7.45 (5 H, m), 8.07 (IH, d), 8.80 to 9.50 (IH, d).

(b) 8-Hydroxy-5 - [('R' ^- hydroxy-2- (2-methylindan-2-ylamino) ethyl])

-iŕí-quinolin-2-one

The product of Example 27 (a) (100 mg, 0.22 mmol) was dissolved in methanol (20 mL) and the protecting group was removed by adding a catalytic amount of 10% palladium on carbon and stirring for 1 hour under a hydrogen atmosphere. The catalyst was filtered off, the solvent was evaporated to give the product as a yellow solid.

1 H-NMR (d ₄ -CH ₃ OH) ppm: 1.20 (3H, s), 2.75 (4H, m), 2.95 (2H, d),

5.03 (1H, m), 6.60 (IH, d), 6.82 (IH, d), 7.00 (4H, m), 7.08 (IH, d), 8.20 (IH, d) , d).

Example 28

5- [2- (5,6-diethyl-indan-2-ylamino) ethyl] -8-hydroxy-itf-quinolin-2-one

This compound was prepared from the product of Example 2 by the procedure of Temple et al., Med. Chem., 19, 626-633 (1976).

¹ H NMR (d ₄ -CH ₃ OH) ppm: 1.08 (3H, t), 2.55 (4H, q), 2.96 (2H, dd),

3.18 (4H, m), 3.28 (2H, dd), 3.99 (IH, m), 6.60 (IH, d), 6.90 (IH, d), 6.97 (IH) d), 7.00 (2H, s), 8.07 (1H, d).

Example 29 (a) 8-Benzyloxy-5 - [(R) -1-hydroxy-2- (2-methyl-2,3,5,6,7,8-hexahydro-2H-cyclopenta [b] naphthaler). -2-ylamino) ethyl] -1H-quinolin-2-one

The title compound was prepared from 8-benzyl oxy-5- (R) -oxiranyl-1H-quinolin-2-one (220 g) and Intermediate 24 (150 mg) by the procedure of Example 27 (a).

1 H-NMR (CDCl ₃ ) ppm: 1.37 (IH, s), 1.78 (4H, m), 2.10 (2H, br s), 2.72 (5 H, m), 2.80 (2H, dd) 2.95 (3H, m), 5.08 (1H, m ), 5.17 (2H, s) 6.65 (IH, d), 6.88 (2H, s), 7.02 (2H, d), 7.26 ( IH, d) 7.40 (5 H, m), 8.05 (1 H, d).

(b) 8-Hydroxy-5 - [(R) -1'-hydroxy-2- (2-methyl-2,3,5,6,7,8-hexa62-hydro-2H-cyclopenta [b] naphthalene- 2-ylamino) ethyl] -1H-quinolin-2-one

The title compound was prepared by hydrogenating the product of Example 29 (a) using the procedure of Example 27 (b). The product was purified by high pressure liquid chromatography (gradient elution with H ₂ O, CH ₃ CN, CF ₃ COOH).

NMR (D _II CH ₃ OH) ppm (TFA salt): 1.65 (3H, s), 1.85 (4H, m), 2.85 (4H, m), 3.15 (2H, m) 3.40 (4H, m), 5.48 (1H, t), 6.83 (1H, d), 7.03 (2H, s), 7.15 (1H, d), 7.45 (1H, m) 1H, d), 8.40 (1H, d).

Example 30 (a) 5 - {(S) -2- [Benzyl- (2,3,5,6,7,8-hexahydro-2H-cyclopenta [b] naphthalen-2-yl) amino] -1-hydroxyethyl 8-Benzyloxy-1H-quinolin-2-one

A mixture of Intermediate 16 (150 mg) and benzyl- (2,3,5,6,7,8-hexahydro-1H-cyclopenta [b] naphthalen-2-yl) amine (142 mg) in toluene (1 mL) was heated. 36 hours at 80 ° C. The residue was purified by chromatography (silica gel, chloroform / ethanol 20: 1) to give the product as a yellow foam.

NMR (CDCl 3) ppm: 1.77 (4H, m), 2.72 (6H, m), 3.01 (4H, m), 3.70 (1H, d), 3.88 (IH, d) 4.82 (1H, m), 5.15 (2H, s), 6.50 (1H, d), 6.8-8.00 (13H, m), 9.05 (1H, br s) .

(b) 5 - [(S) -2- (2,3,5,6,7,8-Hexahydro-2H-cyclopenta [b] naphthalen-2-yl) amino) -1-hydroxyethyl] -8-hydroxy -22í-quinolin-2-one

A solution of the product of Example 30 (a) (150mg) in methanol (20ml) was stirred at room temperature under a hydrogen atmosphere in the presence of 10% palladium on carbon for 5 hours. The reaction mixture was filtered and the product was purified by chromatography (silica gel, chloroform / ethanol 20: 1) followed by crystallization from methanol.

NMR (d ₄ -CH ₃ OH) ppm: 1.65 (4H, m), 2.57 (4H, m), 2.86 (2H, dd),

3.10 (4H, m), 3.82 (1H, m), 5.25 (IH, m), 6.55 (IH, d), 6.78 (2H, s), 6.91 (IH) , d), 7.19 (1H, d), 8.27 (1H, d).

Example 31 (a) Acetic acid (R) -2- [benzyl- (2-methylindan-2-yl) amino] -1- (4-benzyloxy-3-methanesulfonylaminophenyl) ethyl ester

The title compound was prepared from Intermediate 27 (476 mg), triethylamine (231 mg) and methanesulfonyl chloride (210 mg) according to the procedure of Example 25 (b). TLC (silica gel, n-hexane / ethyl acetate 2: 1 Rf = 0.45).

(b) N-5 - {(R) - [Benzyl- (2-methylindan-2-yl) amino] -1-hydroxyethyl} benzyloxyphenyl) methanesulfonamide

The product of Example 31 (a) (200 mg) was dissolved in methanol (8 mL), potassium carbonate (138 mg) was added followed by dropwise addition of water (2 mL). The reaction mixture is further stirred at room temperature. TLC indicated complete reaction after 24 hours. Ethyl acetate (100 mL) was added and the solution was washed with water (50 mL) and brine (50 mL). The organic phase is dried over magnesium sulphate, filtered and the solvent is evaporated off under vacuum. The product was purified by flash column chromatography (silica gel, n-hexane / ethyl acetate 3: 1). TLC (silica gel, n-hexane / ethyl acetate 2: 1 Rf = 0.35).

(c) N- {2-Hydroxy-5 - [(R) -1-hydroxy-2- (2-methylindan-2-yl) amino] ethyl} phenyl} methanesulfonamide

The title compound was prepared from the product of Example 31 (b) according to the procedure of Example 1 (b). TLC (silica gel, dichloromethane / methanol 10: 1 Rf = 0.10).

Example 32 (a) Acetic acid (R) -2- [benzyl- (2-methylindan-2-yl) amino] -1- (4-benzyloxy-3-ethanesulfonylaminophenyl) ethyl ester

The title compound was prepared from Intermediate 27, triethylamine (242 mg) and ethanesulfonyl chloride (247 mg) according to the procedure of Example 25 (b). TLC (silica gel, n-hexane / ethyl acetate 2: 1)

Rf = 0.50).

(b) 5 - ((R) -2- [Benzyl- (2-methylindan-2-yl) amino] -1-hydroxyethyl} -2-benzyloxyphenyl) ethanesulfonamide

The title compound was prepared from the product of Example 32 (a) following the procedure of Example 31 (b). TLC (silica gel, n-hexane / ethyl acetate 2: 1 Rf = 0.40).

(c) {2-Hydroxy-5 - [(R) -1'-hydroxy-2- (2-methylindan-2-ylamino) ethyl] phenyl} ethanesulfonamide

The title compound was prepared from the product of Example 32 (b) according to the procedure of Example 1 (b). TLC (silica gel, dichloromethane / methanol 10: 1 Rf = 0.10).

Example 33 (a) (R) -2- [benzyl- (2-methylindan-2-yl) amino] -1- [4-benzyloxy-3- (propane-1-sulfonylamino) phenyl] ethyl acetate

The title compound was prepared from Intermediate 27 (525 mg), triethylamine (255 mg) and 1-propanesulfonyl chloride (288 mg) according to the procedure of Example 25 (a). TLC (silica gel, n-hexane / ethyl acetate 4: 1 Rf = 0.25).

(b) (5- (R) -2- [Benzyl- (2-methylindan-2-yl) amino] -1-hydroxyethyl} benzyloxyphenyl) propane-1-sulfonamide

The title compound was prepared from the product of Example 33 (a) following the procedure of Example 31 (b). TLC (silica gel, n-hexane / ethyl acetate 4: 1 Rf = 0.15).

(c) (2-Hydroxy-5 - [(R) -1-hydroxy-2- (2-methylindan-2-ylamino) ethyl] phenyl} propane-1-sulfonamide

The title compound was prepared from the product of Example 33 (b) according to the procedure of Example 1 (b). TLC (silica gel, dichloromethane / methanol 10: 1 Rf = 0.05).

Example 34 (a) N- {2-Benzyloxy-5 - [(2-ethylindan-2-ylamino) acetyl] phenyl} methanesulfonamide

The reaction mixture of 2-ethylindan-2-ylamine and N-2-benzyloxy-5-bromoacetylphenyl) methanesulfonamide in acetonitrile is stirred for 20 hours at room temperature. The product is isolated by filtration. ES ⁺ MS m / e = 479 (MH &lt; ^{+ &gt;} ).

(b) N- (2-Benzyloxy-5- [2- (2-ethylindan-2-ylamino) -1-hydroxyethyl] phenyl) methanesulfonamide

The product of Example 34 (a) is suspended in a mixture of ethanol and dichloromethane. Sodium borohydride is added at 0 ° C and the mixture is stirred at room temperature for 3 hours, then filtered and column chromatography (silica gel, ethyl acetate / ethanol 4: 1) gives the product as a white foam. ES ⁺ MS m / e = 480 (MH &lt; + &gt;).

(c) N- {5- [2- (2-ethylindan-2-ylamino) -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide

The product of Example 34 (b) in methanol (20 mL) was stirred under an atmosphere of hydrogen at room temperature. 18 hours in the presence of 10% palladium on carbon. The mixture was filtered through a pad of Celite, the filtrate was concentrated in vacuo and then chromatographed (silica gel, ethyl acetate / ethanol 2: 1). Trituration in ether / ethyl acetate gave the product as off-white crystals (100 mg).

1 H NMR (d ₄ -CH ₃ OH) ppm: 0.85 (3H, t), 1.65 (2H, m), 2.75 (2H, m),

2.85 (3H, s), 2.95 (4H, m), 6.80 (1H, d), 7.05 (5H, m), 7.30 (1H, s).

ES ⁺ MS m / e = 491 (MH &lt; ^{+ &gt;} ).

Example 35 (a) (R) -1- (4-Benzyloxy-3-methanesulfonylaminophenyl) -2- [benzyl- (2,5,6-trimethylindan-2-yl) amino] ethyl acetate

To a solution of Intermediate 29 in dichloromethane and triethylamine was added methanesulfonyl chloride at room temperature and the reaction mixture was stirred for 18 hours. It is then washed with 0.2 N hydrochloric acid, saturated sodium bicarbonate solution and brine. The product is purified by chromatography (silica gel, ethyl acetate / hexane 1: 4). ES 'MS m / e = 625 (M').

(b) N- (2-Benzyloxy-5 - {(R) -2- [benzyl (2,5,6-trimethylindan-2-yl) amino] -1-hydroxyethyl} phenyl) methanesulfonamide

The product of Example 35 (a) was stirred for 3 days in a mixture of methanol and water with potassium carbonate, followed by evaporation of the solvent in vacuo. The product is purified by chromatography (silica gel, ethyl acetate / hexane 1: 2).

^X 1 HNMR (CDCl ₃₎ ppm: 1.21 (3H, s), 2.22 (6H, s), 2.63-2.82 (4H, m), 2.84 (3H, s), 3 20 (2H, br d), 3.61 (IH, d), 3.64 (IH, br s), 3.83 (IH, m), 4.08 (IH, d), 5.09 ( 2H, s), 6.75 (NH, br s), 6.90-7.05 (4H, m), 7.25-7.45 (11H).

(c) N- {2-Hydroxy-5 - [(R) -1,1-hydroxy-2- (2,5,6-trimethylindan-2-yl) amino] -1-hydroxyethyl] phenyl} methanesulfonamide

The title compound was prepared from the product of Example 35 (b) following the procedure of Example 34 (c).

ES + MS m / e = 405 (MH +).

Claims (14)

Compounds of formula I, R ⁵ 'R ⁶ (Γ in free form, in the form of salts or in the form of solvates, in which: Ar is a group of formula (II): R ¹ is a hydrogen atom, a hydroxyl group or an alkoxy group, R ² and R ³ are independent of each other hydrogen atoms or an alkyl group, R ⁴ , R ³ , R 0 including and R 'are independently selected from hydrogen, halogen, cyano, hydroxyl, alkoxy, aryl, alkyl, alkyl substituted with one or more halogen atoms, once or more hydroxy or alkoxy groups, alkyl interrupted by one or more hetero atoms, alkenyl, triaikylsilylovú group, a carboxyl group, an alkoxycarbonyl group or a -CONR ⁿ R ^12, wherein R ¹¹ and R ¹² are independently H or C a group or substituents R ⁴ and R ⁵ , R ⁵ and R ⁶ or R ⁶ and R 1 together with the carbon atom to which they are attached represent a carbocyclic or heterocyclic ring, R ³ is halogen, -OR ¹³ , -CH ₂ OR ^13, or -NHR ' ³ , wherein R ¹³ is hydrogen, alkyl, alkyl interrupted by one or more heteroatoms, -COR ¹⁴ , wherein R ¹⁴ is hydrogen, -N (R ¹⁵ ) R ¹⁰ , alkyl or alkyl interrupted by one or more heteroatoms, or aryl and R 'and R' are independently hydrogen, alkyl, or alkyl interrupted by one or by more heteroatoms, or R ¹³ is -C (= NH) R ¹⁷ , -SOR ^17, or -SO ₂ R ¹⁷ , wherein R ¹⁷ is an alkyl or alkyl group interrupted by one or more heteroatoms, and R 'is H or R ⁸ is -NHR ¹⁸ where -NHR ¹⁸ and R ⁹ together with the carbon to which they are attached represent 5aiebo 6-membered heterocyclic ring, R ' ^J is -OR ¹⁹ or -NHR ¹⁹ wherein R ¹⁹ is hydrogen, alkyl, alkyl interrupted by one or more heteroatoms, or -COR ²⁰ wherein R ²⁰ is -N (R ¹ ) R ^22, alkyl or alkyl interrupted by one or more heteroatoms or aryl group and R, ⁿ and R ²² are independently H, alkyl or alkyl interrupted by one or more heteroatoms. X is a halogen atom or a halomethyl group or an alkyl group, Y is a carbon atom or atom nitrogen, n is a 1 or 2 P is a zero, h event that Y is a nitrogen atom or 1, that Y is an atom alkyl, q and r are zero or 1, wherein the sum of q + r is 1 or 2 and the asterisk * has the R or S configuration, or mixtures thereof, when R 1 is a hydroxyl group or an alkoxy group. Compounds of formula I according to claim 1, in which Ar is a group of formula II, according to claim 1, in which Y is a carbon atom, R ⁸ is -NHR ¹⁸ and -NHR ¹⁸ together with R ⁹ represent -NH-CO-R ²³ where R ²³ is alkylene, alkenylene or alkyleneoxy, -NH-SO 2 -R ²⁴ wherein R ²⁴ is alkyleneoxy, -NH-R ²⁵ (COOR ²⁶ ), wherein R ²⁵ is alkylene or alkenylene and R ²⁶ is alkyl, or -NH-CO-NH- or -NH-CO- WITH-, R ¹⁰ is OR ¹⁹ where R ¹⁹ is as defined in claim 1, X is an alkyl group, p is 1, q is 1 and r is zero or 1. Compounds of formula I according to claim 2, in which Ar is a group of formula III, IV, V, VI or VII R31 HO R30 (III) Where R ', R and R are independently hydrogen or C1-C4 alkyl, (IV) (V) (VI) ο (wherein Z is O, S, or -NH-. Compounds of formula I according to claim 1, in which Ar is a group of formula II in which Y represents a carbon atom, R ⁸ is a group -CH 2 OR ¹³ , wherein R ¹³ is a hydrogen atom, an alkyl group having 1 to 4 atoms R ⁵ is hydrogen, R ¹⁰ is -OR ¹⁹ , where R ¹⁹ is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxyalkyl; 4 carbon atoms in each alkyl or R ¹⁰ is -NHR ¹⁹ where R ¹⁹ is hydrogen, C 1 -C 4 alkyl, or -COR ²⁰ wherein R ²⁰ is C 1 -C 4 alkyl, (C 6 -C 10) aryl or -N (R ²¹ ) R ²² , wherein R ²¹ and R ²² are each independently hydrogen or C 1 -C 4 alkyl, and p and q are both 1 and n are zero or a group of formula (II) in which Y is a nitrogen atom, R ^a is a group A; -CH ₂ OR ¹³ wherein R ¹³ is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxyalkyl in each alkyl, R ¹⁰ is -OR ¹⁹ , R ¹⁹ is hydrogen, (C 1 -C 4) alkyl or (C 1 -C 4) alkoxyalkyl in each of alkyl, par are zero and q is 1, with Ar being preferred groups of formulas XII, XIII, XIV (XII) (XIII) (XIV) Compounds of formula I according to claim 1, in which Ar is a group of formula II in which Y is a carbon atom, R ⁸ is a group -NHR ¹³ , wherein R ¹³ is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, (C 1 -C 10) alkyl interrupted by 1 to 3 heteroatoms, -COR ¹⁴ wherein R ¹⁴ is hydrogen, (C 1 -C 10) alkyl or (C 1 -C 10) alkyl interrupted by (1 to 3 heteroatoms), or R ¹³ is -C (= NH) R ¹⁷ , -SOR ¹⁷ or -SO ₂ R ¹⁷ wherein R ¹⁷ is C 1 -C 10 alkyl or C 1 -C 10 alkyl interrupted by 1 to 3 by heteroatoms, R ^{9 * 7} is hydrogen, R ~ is a group -OR, wherein R ^- is hydrogen, alkyl of 1 to 4 carbon atoms or alkoxyalkyl having 1 to 4 carbon atoms in each alkyl, p and q are both cases 1 and r are zero, with Ar being the preferred groups of formula XV, R13 / H N - (XV) HO — Z \ Compounds of the formula of the preceding claims, wherein according to any one of R and R, the substituents are identical, namely a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms and either R ⁵ and R ⁵ are identical substituents and it is H, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or alkoxyalkyl having 1 to 4 carbon atoms in each alkyl, or R ⁵ and R ⁶ together represent - (CH2) s ^- or -O (CH 2) 10 -, wherein s is 3 or 4 and t is 1 or 2. Compounds of formula I according to claim 1, in which Ar is a group of formula III, IV, or V, as specified in claim 3, a group of formula XII, as specified in claim 4, or a group of formula XV, such as specified in claim 5, R ¹ is a hydroxyl group, R ² and R ³ are hydrogen atoms and R ⁴ and R ⁴ 'are identical substituents, namely a hydrogen atom, a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group and R ⁵ and R ⁵ are identical substituents and represent a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group or a C 1 -C 4 alkoxyalkyl group in each alkyl moiety; or R ⁵ and R ⁶ together represent a group - (0¾) 4- or -O (CH ₂₎ 2 O-, in free form or in salt form or as a solvate. Compounds of formula I according to any one of the preceding claims, wherein R ¹ is a hydroxyl group or an alkoxy group and the carbon atom marked with an asterisk * in the formula I has the R configuration. Compounds of formula I in free or salt form or solvate form, (A) wherein Ar is a group of formula III wherein all three substituents R ²⁹ , R ³⁰ and R ³¹ are hydrogen, R ¹ is a hydroxyl group, both substituents R ² and R ³ are hydrogen atoms and (i) n is 1 and both substituents R ⁴ and R ⁷ are methoxy and both substituents R ³ and R ⁶ are hydrogen atoms, or (ii) n is 1, and the two substituents R ⁴ and R ⁷ are hydrogen and two substituents R ⁵ and R ^s are CH ₃ CH ₂ -, or (iii) n is 1, both of the substituents R ⁴ and R ⁷ are hydrogen, and both of R ⁵ and R ⁶ are CH ₃ -, or (iv) n is 1, both R ⁴ and R ⁷ are CH ₃ CH ₂ -, and both R ⁵ and R ⁶ are hydrogen, or (v) ) n is 1 and both R ⁴ and R ⁷ are hydrogen and R ⁵ and R ⁶ together are - (CH ₂ ) ₄ -, or (vi) n is 1 and both R ⁴ and R ⁷ are atoms H and R ⁵ and R ⁶ together denote -O (CH _{2) 2} O- ^_, or (vii) n is 1, and the two substituents R ⁴ and R ⁷ are hydrogen and two substituents R ⁵ and R ⁶ represent an CH ₃ (CH ₂ ) ₃ -, or (viii) n is 1 and both R ⁴ and R 'are hydrogen and both R ⁵ and R 0 are CH ₃ (CH ₂ ) ₂ -f or (ix) n is 2 and R ⁴ , R ⁵ , R ⁶ , R ⁷ are hydrogen, or (x) n is 1 and both R ⁴ and R 'are hydrogen and both R ⁵ and R 0 are CH ₃ OCH ₂ -, or (B) wherein: Ar is a group of formula XV R13 / H N where R ¹ 'is hydrogen, R ^x is hydroxyl, R ² and R ³ are hydrogen, R ^{4 and} R ⁷ are hydrogen, R ⁵ and R ⁶ are hydrogen and n is 1, or (C) is a compound selected from the group consisting of 8-hydroxy-5- [1-hydroxy-2- (indan-2-ylamino) ethyl] -1H-quinolin-2-one; 5- [2- (5,6-dimethoxyindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-lH-quinolin-2-one, 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-3-methyl-2H-quinolin-2-one, 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl] -8-methoxymethoxy-6-methyl-2H-quinolin-2-one, 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-6-methyl-2H-quinolin-2-one, 8-hydroxy-5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -3,4-dihydro-2H-quinolin-2-one, N- {2-hydroxy-5 - [(R) -1-hydroxy-2- (2,5,6-trimethylindan-2-ylamino) ethyl] phenyl} formamide, 5 - [(R) -2- (5,6-Diethyl-2-methylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one, (S) -5- [ 2- (4,7-Diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one hydrochloride, 5 - [(R) -1-hydroxy-2- (6,7,8,9-tetrahydro-572-benzocyclohepten-7-ylamino) ethyl] -8-hydroxy-2H-quinolin-2-one hydrochloride, (R) ) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one maleate, 6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-2H-quinolin-2-one hydrochloride, N- [5 - [(R) -2- (5'-diethylenedan-2-ylamino) -1-hydroxyethyl] -2-hydroxyphenyl} formamide, 4 - [(R) -2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -2-dimethyl aminophenol hydrochloride, 4 - [(R) -2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -2-methylaminophenol hydrochloride, N- {5- [2- (5,6-Diethylindan-2-ylamino) -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride, (R) -8-hydroxy-5 - [(S) -1-hydroxy-2] - (4,5,6,7-tetramethyl-2 ~ indan-ylamino) -ethyl] -2-quinolin-2-one, 8-hydroxy-5 - [(R) -1-hydroxy-2- (2-methylindan-2-ylamino) ethyl] -1H-quinolin-2-one, 5- [2- (5,6-Diethylindan-2-ylamino) ethyl] -8-hydroxy-1H-quinolin-2-one, 8-hydroxy-5 - [(R) -1-hydroxy-2- (2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta [b] naphthalen-2-ylamino) ethyl ] -lH-quinolin-2-one, 5 - [(S) -2- (2,3,5,6,7,8-hexahydro-2H-cyclopenta [b] naphthalen-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinoline -2-one, N - (2-hydroxy-5 - [(R 1 -hydroxy-2- (2-methylindan-2-ylamino) ethyl] phenyl] methanesulfonamide, {2-hydroxy-5 - [(R) -1-hydroxy- 2- (2-methylindan-2-ylamino) ethyl] 77 phenyljamide ethanesulfonate, (2-hydroxy-5 - [(R) -1-hydroxy-2- (2-methylindan-2-ylamino) ethyl] phenyl) amide propane-1-sulfonate . N- {5- [2- (2-ethylindan-2-ylamino) -1-hydroxyethyl] -2-hydroxyphenyl} methanesulfonamide, N- {2-hydroxy-5 - [(R) -1-hydroxy-2- (2,5,6-trimethylindan-2-ylamino) ethyl] phenyl} methanesulfonamide. Compounds according to claim 1 in combination with a stereoidic agent, a dopamine receptor agonist or an anticholinergic or antimuscarinic agent. A pharmaceutical composition comprising any compound according to claims 1 to 10, optionally together with a pharmaceutically acceptable carrier. Use of the compounds according to claims 1 to 10 for the preparation of medicaments for the treatment of preventable or ameliorated conditions by activation of β 2 -adrenoreceptor. Use of the compounds according to claims 1 to 10 for the preparation of medicaments for healing roads. obstructive or inflammatory diseases respiratory 14. Method preparation of compounds of general formula of formula I in free or in the form of salts or in the form of solvates, v y z n a - ignating by that is (a) for the preparation of compounds of formula I wherein R ¹ is a hydroxyl group, or (i) reacting a compound of formula XVI A r ¹ -C HC H — R ² (XVI) with a compound of formula XVII (XVII) wherein Ar ¹ is as defined for Ar as defined in claim 1, or in a protective form, R ² , R ³ , R ⁴ , R ⁵ , R ⁵ , R ⁷ and n are as defined in claim 1 and R ³² is a hydrogen atom or an amino protecting group, or (ii) reduces a compound of formula XVIII (XVIII) wherein Ar ¹ is as defined for Ar as defined in claim 1, or a protected form, R ^2, R ^J, R ^4, R ^3, R and R 'are as defined in paragraph 1 and converted to the indicated keto group -CH (OH) - or (b) for the preparation of compounds of the formula I in which R * is a hydrogen atom, a corresponding compound of the formula I in which R ¹ is a hydroxyl group is reduced, or (c) for the preparation of the compounds of formula I in which R is an alkoxy group or (i) O-alkyls the corresponding compound of formula I wherein R ¹ is a hydroxyl group or (ii) reacting a corresponding compound which contains a leaving group instead of R ¹ with an alcohol of the formula !! ^R1, wherein ^R1 is alkoxy, and the resulting compound of formula I in protected form may be converted into a corresponding compound in unprotected form, and the resulting compound of formula I is isolated in free form or in salt or solvate . 15. Compounds of formula XVII (XVII) wherein R ^3, R ^4, R ^5, R ^6, R ⁷ and n are as defined in Claim 1, wherein R ^{4, R:} R and R 'to the benzene ring attached as symmetric substituents and R ³² is a hydrogen atom or an amino protecting group, except for compounds wherein R ⁴ , R ⁵ , R 0, R ⁷ and R ³² are hydrogen atoms, where R ⁴ and R ⁷ are methyl or methoxy groups in wherein R ⁵ , R 0 and R ^{j 2} are hydrogen atoms and wherein R ⁴ , R 5 and R ^{j 2} are hydrogen atoms, when R ^d and R ^c are hydroxyl groups, fluorine atoms or chlorine atoms.